3-(benzoimidazol-2-yl)-indazole inhibitors of the wnt signaling pathway and therapeutic uses thereof

ABSTRACT

Indazole compounds for treating various diseases and pathologies are disclosed. More particularly, the present disclosure concerns the use of an indazole compound or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, Alzheimer&#39;s disease, lung disease and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases and neurological conditions/disorders/diseases due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Also provided are methods for treating Wnt-related disease states.

RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 14/149,948, filed Jan. 8, 2014, and claims the benefit of U.S.Provisional Application No. 61/750,221, filed Jan. 8, 2013, each ofwhich is incorporated herein by reference in its entirety.

BACKGROUND Technical Field

This disclosure relates to inhibitors of one or more proteins in the Wntpathway, including inhibitors of one or more Wnt proteins, andcompositions comprising the same. More particularly, it concerns the useof an indazole compound or salts or analogs thereof, in the treatment ofdisorders characterized by the activation of Wnt pathway signaling(e.g., cancer, abnormal cellular proliferation, angiogenesis,Alzheimer's disease, lung disease, and osteoarthritis), the modulationof cellular events mediated by Wnt pathway signaling, as well as geneticdiseases and neurological conditions/disorders/diseases due to mutationsor dysregulation of the Wnt pathway and/or of one or more of Wntsignaling components. Also provided are methods for treating Wnt-relateddisease states.

Background

The Wnt growth factor family includes more than 10 genes identified inthe mouse and at least 19 genes identified in the human. Members of theWnt family of signaling molecules mediate many short- and long-rangepatterning processes during invertebrate and vertebrate development. TheWnt signaling pathway is known for its role in the inductiveinteractions that regulate growth and differentiation, and it also playsroles in the homeostatic maintenance of post-embryonic tissue integrity.Wnt stabilizes cytoplasmic β-catenin, which stimulates the expression ofgenes including c-myc, c jun, fra-1, and cyclin Dl. In addition,misregulation of Wnt signaling can cause developmental defects and isimplicated in the genesis of several human cancers. More recently, theWnt pathway has been implicated in the maintenance of stem or progenitorcells in a growing list of adult tissues that now includes skin, blood,gut, prostate, muscle and the nervous system.

SUMMARY

The present disclosure provides methods and reagents, involvingcontacting a cell with an agent, such as an indazole compound, in asufficient amount to antagonize a Wnt activity, e.g., to reverse orcontrol an aberrant growth state or correct a genetic disorder due tomutations in Wnt signaling components.

Some embodiments disclosed herein include Wnt inhibitors containing anindazole core. Other embodiments disclosed herein include pharmaceuticalcompositions and methods of treatment using these compounds.

One embodiment disclosed herein includes compounds of Formula I:

In some embodiments of Formula (I):

R¹ is -heteroarylR³R⁴;

R² is selected from the group consisting of H, halide, C₁₋₃ alkyl, —CN,—OR⁸, —OH, —(C₁₋₃ alkyl)OR⁸, —NR⁹R¹⁰, —(C₁₋₃ alkyl)NR⁹R¹⁰,-heteroarylR⁵, -heterocyclylR⁶ and -arylR⁷;

R³ is 1 substituent attached to the heteroaryl ring and is selected fromthe group consisting of H, C₁₋₃ alkyl, —CF₃, —NR⁹R¹⁰, —NHC(═O)R⁸, —(C₁₋₃alkyl)heterocyclylR⁶ and —(C₁₋₃ alkyl)NR⁹R¹⁰;

R⁴ is 1 substituent attached to the heteroaryl ring and is selected fromthe group consisting of H, C₁₋₃ alkyl, —CF₃, halide, —CN, —OR⁸, —OH,—(C₁₋₃ alkyl)OR⁸, —NR⁹R¹⁰, —(C₁₋₃ alkyl)NR⁹R¹⁰ and —OCF₃;

R⁵ is 1-3 substituents attached to the heteroaryl ring and each isindependently selected from the group consisting of H, C₁₋₃ alkyl, —CF₃,halide, —CN, —OR⁸, —OH, —(C₁₋₃ alkyl)OR⁸, —NR⁹R¹⁰, —(C₁₋₃ alkyl)NR⁹R¹⁰and —OCF₃;

R⁶ is 1-3 substituents attached to the heterocyclyl ring and each isindependently selected from the group consisting of H, C₁₋₃ alkyl, —CF₃,halide, —CN, —OR⁸, —OH, —(C₁₋₃ alkyl)OR⁸, —NR⁹R¹⁰, —(C₁₋₃ alkyl)NR⁹R¹⁰and —OCF₃;

R⁷ is 1-3 substituents attached to the aryl ring and each isindependently selected from the group consisting of H, C₁₋₃ alkyl, —CF₃,halide, —CN, —OR⁸, —OH, —(C₁₋₃ alkyl)OR⁸, —NR⁹R¹⁰, —(C₁₋₃ alkyl)NR⁹R¹⁰and —OCF₃;

each R⁸ is independently selected from the group consisting of C₁₋₉alkyl, -heteroarylR¹², -heterocyclylR¹³, -arylR¹⁴, carbocyclylR¹¹,—(C₁₋₃ alkyl)heteroarylR¹², —(C₁₋₃ alkyl)heterocyclylR¹³, —(C₁₋₃alkyl)arylR¹⁴ and —(C₁₋₃ alkyl)carbocyclylR¹¹; each R⁹ is independentlyselected from the group consisting of H, C₁₋₆ alkyl, -heteroarylR¹²,-heterocyclylR¹³, -arylR¹⁴, carbocyclylR¹¹, —(C₁₋₃ alkyl)heteroarylR¹²,—(C₁₋₃ alkyl)heterocyclylR¹³, —(C₁₋₃ alkyl)arylR¹⁴ and —(C₁₋₃alkyl)carbocyclylR¹¹;

each R¹⁰ is independently selected from the group consisting of H andC₁₋₆ alkyl; or

R⁹ and R¹⁰ are optionally linked to form a five or six memberedheterocyclyl ring;

R¹¹ is 1-3 substituents attached to the carbocyclyl ring and eachindependently selected from the group consisting of H, C₁₋₃ alkyl, —CF₃,halide, —CN, —O(R¹⁰), —(C₁₋₃ alkyl)OR¹⁰, —N(R¹⁰)₂, —(C₁₋₃ alkyl)N(R¹⁰)₂and —OCF₃;

R¹² is 1-3 substituents attached to the heteroaryl ring and eachindependently selected from the group consisting of H, C₁₋₃ alkyl, —CF₃,halide, —CN, —O(R¹⁰), —(C₁₋₃ alkyl)OR¹⁰, —N(R¹⁰)₂, —(C₁₋₃ alkyl)N(R¹⁰)₂and —OCF₃;

R¹³ is 1-3 substituents attached to the heterocyclyl ring and eachindependently selected from the group consisting of H, C₁₋₃ alkyl, —CF₃,halide, —CN, —O(R¹⁰), —(C₁₋₃ alkyl)OR¹⁰, —N(R¹⁰)₂, —(C₁₋₃ alkyl)N(R¹⁰)₂and —OCF₃;

R¹⁴ is 1-3 substituents attached to the aryl ring and each independentlyselected from the group consisting of H, C₁₋₃ alkyl, —CF₃, halide, —CN,—O(R¹⁰), —(C₁₋₃ alkyl)OR¹⁰, —N(R¹⁰)₂, —(C₁₋₃ alkyl)N(R¹⁰)₂ and —OCF₃;

with the proviso that a compound of Formula I is not a compound selectedfrom the group consisting of:

Some embodiments include stereoisomers and pharmaceutically acceptablesalts of a compound of Formula (I).

Some embodiments include pro-drugs of a compound of Formula (I).

Some embodiments of the present disclosure include pharmaceuticalcompositions comprising a compound of Formula (I) and a pharmaceuticallyacceptable carrier, diluent, or excipient.

Other embodiments disclosed herein include methods of inhibiting one ormore members of the Wnt pathway, including one or more Wnt proteins byadministering to a patient affected by a disorder or disease in whichaberrant Wnt signaling is implicated, such as cancer and other diseasesassociated with abnormal angiogenesis, cellular proliferation, cellcycling and mutations in Wnt signaling components, a compound accordingto Formula (I). Accordingly, the compounds and compositions providedherein can be used to treat cancer, to reduce or inhibit angiogenesis,to reduce or inhibit cellular proliferation and correct a geneticdisorder due to mutations in Wnt signaling components.

Non-limiting examples of diseases which can be treated with thecompounds and compositions provided herein include a variety of cancers,diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, sepsis,anklyosing spondylitism, psoriasis, scleroderma, mycotic and viralinfections, osteochondrodysplasia, Alzheimer's disease, lung disease,osteoarthritis, articular cartilage (chondral) defects, degenerativedisc disease (or intervertebral disc degeneration), polyposis coli,osteoporosis-pseudoglioma syndrome, familial exudativevitreoretinopathy, retinal angiogenesis, early coronary disease,tetra-ameliasyndrome, Müllerian-duct regression and virilization, SERKALsyndrome, diabetes mellitus type 2, Fuhrmann syndrome,Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletaldysplasia, focal dermal hypoplasia, autosomal recessive anonychia,neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile Xsyndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome,Beckwith-Wiedemann Syndrome, Norrie disease, and Rett syndrome.

Some embodiments of the present disclosure include methods to preparecompounds of Formula (I).

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION

Compositions and methods for inhibiting one or more members of the Wntpathway, including one or more Wnt proteins are useful.

Some embodiments relate to a method for treating a disease including,but not limited to, cancers, diabetic retinopathy, pulmonary fibrosis,rheumatoid arthritis, sepsis, anklyosing spondylitism, psoriasis,scleroderma, mycotic and viral infections, bone and cartilage diseases,Alzheimer's disease, lung disease, osteoarthritis, articular cartilage(chondral) defects, degenerative disc disease (or intervertebral discdegeneration), polyposis coli, bone density and vascular defects in theeye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudativevitreoretinopathy, retinal angiogenesis, early coronary disease,tetra-amelia, Müllerian-duct regression and virilization, SERKALsyndrome, type II diabetes, Fuhrmann syndrome,Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia,focal dermal hypoplasia, autosomal recessive anonychia, neural tubedefects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICFsyndrome, Angelman's syndrome, Prader-Willi syndrome, Beckwith-WiedemannSyndrome, Norrie disease, and Rett syndrome.

In some embodiments, non-limiting examples of bone and cartilagediseases which can be treated with the compounds and compositionsprovided herein include bone spur (osteophytes), craniosynostosis,fibrodysplasia ossificans progressive, fibrous dysplasia, giant celltumor of bone, hip labral tear, meniscal tears, osteoarthritis,articular cartilage (chondral) defects, degenerative disc disease (orintervertebral disc degeneration), osteochondritis dissecans,osteochondroma (bone tumor), osteopetrosis, relapsing polychondritis,and Salter-Harris fractures.

In some embodiments, pharmaceutical compositions are provided that areeffective for treatment of a disease of an animal, e.g., a mammal,caused by the pathological activation or mutations of the Wnt pathway.The composition includes a pharmaceutically acceptable carrier and acompound as described herein.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this disclosure belongs. All patents, applications,published applications, and other publications are incorporated byreference in their entirety. In the event that there is a plurality ofdefinitions for a term herein, those in this section prevail unlessstated otherwise.

As used herein, “alkyl” means a branched, or straight chain chemicalgroup containing only carbon and hydrogen, such as methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,n-pentyl, iso-pentyl, sec-pentyl, and neo-pentyl. Alkyl groups caneither be unsubstituted or substituted with one or more substituents,e.g., halide, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl,thio, carboxy, carbonyl, benzyloxy, aryl, heteroaryl, or otherfunctionality that may be suitably blocked, if necessary for purposes ofthe disclosure, with a protecting group. Alkyl groups can be saturatedor unsaturated (e.g., containing —C═C— or —C≡C— subunits), at one orseveral positions. Typically, alkyl groups will comprise 1 to 9 carbonatoms (e.g., 1 to 6, 1 to 4, or 1 to 2 carbon atoms).

As used herein, “carbocyclyl” means a cyclic ring system containing onlycarbon atoms in the ring system backbone, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Carbocyclyls mayinclude multiple fused rings. Carbocyclyls may have any degree ofsaturation provided that at least one ring in the ring system is notaromatic. Carbocyclyl groups can either be unsubstituted or substitutedwith one or more substituents, e.g., alkyl, halide, alkoxy, acyloxy,amino, amido, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl,benzyloxy, aryl, heteroaryl, or other functionality that may be suitablyblocked, if necessary for purposes of the disclosure, with a protectinggroup. Typically, carbocyclyl groups will comprise 3 to 10 carbon atoms(e.g., 3 to 6 carbon atoms).

As used herein, “lower alkyl” means a subset of alkyl having 1 to 3carbon atoms, and can be linear or branched. Examples of lower alkylgroups include methyl, ethyl, n-propyl, and isopropyl. Likewise,radicals using the terminology “lower” refer to radicals having 1 toabout 3 carbons in the alkyl portion of the radical.

As used herein, “amido” means a H—CON—, alkyl-CON—, carbocyclyl-CON—,aryl-CON—, heteroaryl-CON—, or heterocyclyl-CON group wherein the alkyl,carbocyclyl, aryl or heterocyclyl group is as herein described.

As used herein, “aryl” means an aromatic radical having a single-ring(e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl)with only carbon atoms present in the ring backbone. Aryl groups caneither be unsubstituted or substituted with one or more substituents,e.g., amino, cyano, hydroxyl, lower alkyl, haloalkyl, alkoxy, nitro,halo, mercapto, and other substituents. An exemplary carbocyclic aryl isphenyl.

As used herein, the term “heteroaryl” means a mono-, bi-, tri- orpolycyclic group having 5 to 14 ring atoms, alternatively 5, 6, 9, or 10ring atoms; having 6, 10, or 14 pi electrons shared in a cyclic array;wherein at least one ring in the system is aromatic, and at least onering in the system contains one or more heteroatoms independentlyselected from the group consisting of N, O, and S. Heteroaryl groups caneither be unsubstituted or substituted with one or more substituents,e.g., amino, cyano, hydroxyl, lower alkyl, haloalkyl, alkoxy, nitro,halo, mercapto, and other substituents. Examples of heteroaryl includethienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl,triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl,benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl,cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl,naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl,pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl,thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl,pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine,pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane,2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole,2,3-dihydrobenzofuran, 2,3-dihydrobenzo[b][1,4]oxathiine, and others.

As used herein, “amide” includes both RNR′CO— (in the case of R=alkyl,alkaminocarbonyl-) and RCONR′— (in the case of R=alkyl,alkylcarbonylamino-). In both cases, R′ ═H or alkyl. In someembodiments, R′ is H.

As used herein, the term “ester” includes both ROCO— (in the case ofR=alkyl, alkoxycarbonyl-) and RCOO— (in the case of R=alkyl,alkylcarbonyloxy-).

As used herein, “acyl” means an H—CO— or alkyl-CO—,carbocyclyl-CO-aryl-CO—, heteroaryl-CO— or heterocyclyl-CO— groupwherein the alkyl, carbocyclyl, aryl or heterocyclyl group is as hereindescribed. In some embodiments, acyls contain a lower alkyl. Exemplaryalkyl acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl,t-butylacetyl, butanoyl, and palmitoyl.

As used herein, “halo”, “halide” or “halogen” is a chloro, bromo,fluoro, or iodo atom radical. In some embodiments, the halide isfluorine.

As used herein, “haloalkyl” means a hydrocarbon substituent, which is alinear or branched or cyclic alkyl, substituted with chloro, bromo,fluoro, or iodo atom(s). In some emdobiments, a haloalkyls arefluoroalkyls, wherein one or more of the hydrogen atoms have beensubstituted by fluoro. Haloalkyls can be of 1 to about 3 carbons inlength, (e.g., 1 to about 2 carbons). In some embodiments, thehaloalkyls are 1 carbon in length.

As used herein, “heterocyclyl” means a nonaromatic cyclic ring systemcomprising at least one heteroatom in the ring system backbone.Heterocyclyls may include multiple fused rings. Heterocyclyls may besubstituted or unsubstituted with one or more substituents, e.g., alkyl,halide, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl, mercapto,carboxy, carbonyl, benzyloxy, aryl, heteroaryl, and other substituents,and are attached to other groups via any available valence (e.g., anyavailable carbon or nitrogen). In some embodiments, heterocycles have5-7 members. In six membered monocyclic heterocycles, the heteroatom(s)are selected from one up to three of O, N or S, and wherein when theheterocycle is five membered, it can have one or two heteroatomsselected from O, N, or S. Examples of heterocyclyl include azirinyl,aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2-dithiazolyl,dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl,morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl,tetrahydrofuryl, tetrahydropyridinyl, oxazinyl, thiazinyl, thiinyl,thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl,piperidinyl, pyrazolidinyl imidazolidinyl, thiomorpholinyl, and others.

As used herein, “substituted amino” means an amino radical which issubstituted by one or two alkyl, cycloalkyl, aryl, heteroaryl, orheterocyclyl groups, wherein the alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl are defined as above.

As used herein, “substituted thiol” refers to an RS— group wherein R isan alkyl, a cycloalkyl, an aryl, heteroaryl, or a heterocyclyl group,wherein the alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl aredefined as above.

As used herein, when two groups are indicated to be “linked” or “bonded”to form a “ring”, it is to be understood that a bond is formed betweenthe two groups and may involve replacement of a hydrogen atom on one orboth groups with the bond, thereby forming a carbocyclyl, heterocyclyl,aryl, or heteroaryl ring. The skilled artisan will recognize that suchrings can and are readily formed by routine chemical reactions, and itis within the purview of the skilled artisan to both envision such ringsand the methods of their formations. In some embodiments, rings havefrom 3-7 members (e.g., 5 or 6 members). As used herein the term “ring”or “rings” when formed by the combination of two radicals refers toheterocyclic, carbocyclic, aryl, or heteroaryl rings.

The skilled artisan will recognize that some structures described hereinmay be resonance forms or tautomers of compounds that may be fairlyrepresented by other chemical structures, even when kinetically, theartisan recognizes that such structures are only a very small portion ofa sample of such compound(s). Such compounds are clearly contemplatedwithin the scope of this disclosure, though such resonance forms ortautomers are not represented herein.

The compounds provided herein may encompass various stereochemicalforms. The compounds also encompass diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds. Separation ofthe individual isomers or selective synthesis of the individual isomersis accomplished by application of various methods which are well knownto practitioners in the art. Unless otherwise indicated, when adisclosed compound is named or depicted by a structure withoutspecifying the stereochemistry and has one or more chiral centers, it isunderstood to represent all possible stereoisomers of the compound.

The term “administration” or “administering” refers to a method ofgiving a dosage of a compound or pharmaceutical composition providedherein to a vertebrate or invertebrate, including a mammal, a bird, afish, or an amphibian, where the method is, e.g., orally,subcutaneously, intravenously, intranasally, topically, transdermally,intraperitoneally, intramuscularly, intrapulmonarilly, vaginally,rectally, ontologically, neuro-otologically, intraocularly,subconjuctivally, via anterior eye chamber injection, intravitreally,intraperitoneally, intrathecally, intracystically, intrapleurally, viawound irrigation, intrabuccally, intra-abdominally, intra-articularly,intra-aurally, intrabronchially, intracapsularly, intrameningeally, viainhalation, via endotracheal or endobronchial instillation, via directinstillation into pulmonary cavities, intraspinally, intrasynovially,intrathoracically, via thoracostomy irrigation, epidurally,intratympanically, intracisternally, intravascularly,intraventricularly, intraosseously, via irrigation of infected bone, orvia application as part of any admixture with a prosthetic device. Themethod of administration can vary depending on various factors, e.g.,the components of the pharmaceutical composition, the site of thedisease, the disease involved, and the severity of the disease.

A “diagnostic” as used herein is a compound, method, system, or devicethat assists in the identification and characterization of a health ordisease state. The diagnostic can be used in standard assays as is knownin the art.

The term “mammal” is used in its usual biological sense. Thus, itspecifically includes humans, cattle, horses, dogs, cats, mice, rats,sheeps, pigs, goats, and non-human primates, but also includes manyother species.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” includes any and all solvents, co-solvents,complexing agents, dispersion media, coatings, isotonic and absorptiondelaying agents and the like which are not biologically or otherwiseundesirable. The use of such media and agents for pharmaceuticallyactive substances is well known in the art. Except insofar as anyconventional media or agent is incompatible with the active ingredient,its use in the therapeutic compositions is contemplated. Supplementaryactive ingredients can also be incorporated into the compositions. Inaddition, various adjuvants such as are commonly used in the art may beincluded. These and other such compounds are described in theliterature, e.g., in the Merck Index, Merck & Company, Rahway, N.J.Considerations for the inclusion of various components in pharmaceuticalcompositions are described, e.g., in Gilman et al. (Eds.) (2010);Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 12thEd., The McGraw-Hill Companies.

The term “pharmaceutically acceptable salt” refers to salts that retainthe biological effectiveness and properties of the compounds providedherein and, which are not biologically or otherwise undesirable. In manycases, the compounds provided herein are capable of forming acid and/orbase salts by virtue of the presence of amino and/or carboxyl groups orgroups similar thereto. Pharmaceutically acceptable acid addition saltscan be formed with inorganic acids and organic acids. Inorganic acidsfrom which salts can be derived include, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike. Organic acids from which salts can be derived include, forexample, acetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Pharmaceutically acceptable base additionsalts can be formed with inorganic and organic bases. Inorganic basesfrom which salts can be derived include, for example, sodium, potassium,lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese,aluminum, and the like. In some embodiments, the bases can be derivedfrom the ammonium, potassium, sodium, calcium, and magnesium salts.Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like, specifically such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine, andethanolamine. Many such salts are known in the art, as described in WO87/05297.

“Solvate” refers to the compound formed by the interaction of a solventand a compound provided herein, a metabolite, or salt thereof. Suitablesolvates are pharmaceutically acceptable solvates including hydrates.

“Patient” or “subject” as used herein, means a human or a non-humanmammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, agoat, a non-human primate or a bird, e.g., a chicken, as well as anyother vertebrate or invertebrate.

By “therapeutically effective amount” or “pharmaceutically effectiveamount” of a compound as provided herein is one which is sufficient toachieve the desired effect and may vary according to the nature andseverity of the disease condition, and the potency of the compound.“Therapeutically effective amount” is also intended to include one ormore of the compounds of Formulas (I) and/or (Ia) in combination withone or more other agents that are effective to inhibit Wnt relateddiseases and/or conditions. In some embodiments, the combination ofcompounds is a synergistic combination. Synergy, as described, forexample, by Chou and Talalay, Advances in Enzyme Regulation (1984), 22,27-55, occurs when the effect of the compounds when administered incombination is greater than the additive effect of the compounds whenadministered alone as a single agent. In general, a synergistic effectis most clearly demonstrated at sub-optimal concentrations of thecompounds. It will be appreciated that different concentrations may beemployed for prophylaxis than for treatment of an active disease. Thisamount can further depend upon the patient's height, weight, sex, ageand medical history.

A therapeutic effect relieves, to some extent, one or more of thesymptoms of the disease, and can include curing a disease. “Curing”means that the symptoms of an active disease are eliminated. However,certain long-term or permanent effects of the disease may exist evenafter a cure is obtained (such as extensive tissue damage).

“Treat,” “treatment,” or “treating,” as used herein refers toadministering a compound or pharmaceutical composition as providedherein for therapeutic purposes. The term “therapeutic treatment” refersto administering treatment to a patient already suffering from a diseasethus causing a therapeutically beneficial effect, such as amelioratingexisting symptoms, preventing additional symptoms, ameliorating orpreventing the underlying metabolic causes of symptoms, postponing orpreventing the further development of a disorder and/or reducing theseverity of symptoms that will or are expected to develop.

Compounds

The compounds and compositions described herein can be used asanti-proliferative agents, e.g., anti-cancer and anti-angiogenesisagents, and/or as inhibitors of the Wnt signaling pathway, e.g., fortreating diseases or disorders associated with aberrant Wnt signaling.In addition, the compounds can be used as inhibitors of one or morekinases, kinase receptors, or kinase complexes. Such compounds andcompositions are also useful for controlling cellular proliferation,differentiation, and/or apoptosis.

Some embodiments of the present disclosure include compounds, salts,pharmaceutically acceptable salts or pro-drug thereof of Formula (I):

In some embodiments of Formula I, R¹ is -heteroarylR³R⁴.

In some embodiments of Formula I, R² is selected from the groupconsisting of H, halide, C₁₋₃ alkyl, —CN, —OR⁸, —OH, —(C₁₋₃ alkyl)OR⁸,—NR⁹R¹⁰, —(C₁₋₃ alkyl)NR⁹R¹⁰, -heteroarylR⁵, -heterocyclylR⁶ and-arylR⁷.

In some embodiments of Formula I, R³ is 1 substituent attached to theheteroaryl ring and is selected from the group consisting of H, C₁₋₃alkyl, —CF₃, —NR⁹R¹⁰, —NHC(═O)R⁸, —(C₁₋₃ alkyl)heterocyclylR⁶ and —(C₁₋₃alkyl)NR⁹R¹⁰.

In some embodiments of Formula I, R⁴ is 1 substituent attached to theheteroaryl ring and is selected from the group consisting of H, C₁₋₃alkyl, —CF₃, halide, —CN, —OR⁸, —OH, —(C₁₋₃ alkyl)OR⁸, —NR⁹R¹⁰, —(C₁₋₃alkyl)NR⁹R¹⁰ and —OCF₃.

In some embodiments of Formula I, R⁵ is 1-3 substituents attached to theheteroaryl ring and each is independently selected from the groupconsisting of H, C₁-3 alkyl, —CF₃, halide, —CN, —OR⁸, —OH, —(C₁₋₃alkyl)OR⁸, —NR⁹R¹⁰, —(C₁₋₃ alkyl)NR⁹R¹⁰ and —OCF₃.

In some embodiments of Formula I, R⁶ is 1-3 substituents attached to theheterocyclyl ring and each is independently selected from the groupconsisting of H, C₁₋₃ alkyl, —CF₃, halide, —CN, —OR⁸, —OH, —(C₁₋₃alkyl)OR⁸, —NR⁹R¹⁰, —(C₁₋₃ alkyl)NR⁹R¹⁰ and —OCF₃.

In some embodiments of Formula I, R⁷ is 1-3 substituents attached to thearyl ring and each is independently selected from the group consistingof H, C₁₋₃ alkyl, —CF₃, halide, —CN, —OR⁸, —OH, —(C₁₋₃ alkyl)OR⁸,—NR⁹R¹⁰, —(C₁₋₃ alkyl)NR⁹R¹⁰ and —OCF₃.

In some embodiments of Formula I, each R⁸ is selected from the groupconsisting of C₁₋₉ alkyl, -heteroarylR¹², -heterocyclylR¹³, -arylR¹⁴,carbocyclylR¹¹, —(C₁₋₃ alkyl)heteroarylR¹², —(C₁₋₃alkyl)heterocyclylR¹³, —(C₁₋₃ alkyl)arylR¹⁴ and —(C₁₋₃alkyl)carbocyclylR¹¹.

In some embodiments of Formula I, each R⁹ is selected from the groupconsisting of H, C₁₋₆ alkyl, -heteroarylR¹², -heterocyclylR¹³, -arylR¹⁴,carbocyclylR¹¹, —(C₁₋₃ alkyl)heteroarylR¹², —(C₁₋₃alkyl)heterocyclylR¹³, —(C₁₋₃ alkyl)arylR¹⁴ and —(C₁₋₃alkyl)carbocyclylR¹¹.

In some embodiments of Formula I, each R¹⁰ is selected from the groupconsisting of H and C₁₋₆ alkyl.

In some embodiments of Formula I, R⁹ and R¹⁰ are linked to form a fiveor six membered heterocyclyl ring.

In some embodiments of Formula I, R¹¹ is 1-3 substituents attached tothe carbocyclyl ring and each independently selected from the groupconsisting of H, C₁₋₃ alkyl, —CF₃, halide, —CN, —O(R¹⁰), —(C₁₋₃alkyl)OR¹⁰, —N(R¹⁰)₂, —(C₁₋₃ alkyl)N(R¹⁰)₂ and —OCF₃;

In some embodiments of Formula I, R¹² is 1-3 substituents attached tothe heteroaryl ring and each is independently selected from the groupconsisting of H, C₁₋₃ alkyl, —CF₃, halide, —CN, —O(R¹⁰), —(C₁₋₃alkyl)OR¹⁰, —N(R¹⁰)₂, —(C₁₋₃ alkyl)N(R¹⁰)₂ and —OCF₃;

In some embodiments of Formula I, R¹³ is 1-3 substituents attached tothe heterocyclyl ring and each is independently selected from the groupconsisting of H, C₁₋₃ alkyl, —CF₃, halide, —CN, —O(R¹⁰), —(C₁₋₃alkyl)OR¹⁰, —N(R¹⁰)₂, —(C₁₋₃ alkyl)N(R¹⁰)₂ and —OCF₃;

In some embodiments of Formula I, R¹⁴ is 1-3 substituents attached tothe aryl ring and each is independently selected from the groupconsisting of H, C₁₋₃ alkyl, —CF₃, halide, —CN, —O(R¹⁰), —(C₁₋₃alkyl)OR¹⁰, —N(R¹⁰)₂, —(C₁₋₃ alkyl)N(R¹⁰)₂ and —OCF₃;

In some embodiments of Formula I, there is the proviso that a compoundof Formula I is not a compound selected from the group consisting of:

Some embodiments of the present disclosure include compounds, salts,pharmaceutically acceptable salts or pro-drug thereof of Formula (Ia):

In some embodiments of Formula Ia, R¹ is -pyridineR³R⁴.

In some embodiments of Formula Ia, R² is selected from the groupconsisting of H, halide, C₁₋₃ alkyl, —CN, —OR⁸, —OH, —(C₁₋₃ alkyl)OR⁸,—NR⁹R¹⁰, —(C₁₋₃ alkyl)NR⁹R¹⁰, -heteroarylR⁵, -heterocyclylR⁶ and-arylR⁷.

In some embodiments of Formula Ia, R³ is 1 substituent attached to theheteroaryl ring and is selected from the group consisting of H, C₁₋₃alkyl, —CF₃, —NR⁹R¹⁰, —NHC(═O)R⁸, —(C₁₋₃ alkyl)heterocyclylR⁶ and —(C₁₋₃alkyl)NR⁹R¹⁰.

In some embodiments of Formula Ia, R⁴ is H.

In some embodiments of Formula Ia, R⁵ is 1-3 substituents attached tothe heteroaryl ring and each is independently selected from the groupconsisting of H, C₁₋₃ alkyl, —CF₃, halide, —CN, —OR⁸, —OH, —(C₁₋₃alkyl)OR⁸, —NR⁹R¹⁰, —(C₁₋₃ alkyl)NR⁹R¹⁰ and —OCF₃.

In some embodiments of Formula Ia, R⁶ is 1-3 substituents attached tothe heterocyclyl ring and each is independently selected from the groupconsisting of H, C₁₋₃ alkyl, —CF₃, halide, —CN, —OR⁸, —OH, —(C₁₋₃alkyl)OR⁸, —NR⁹R¹⁰, —(C₁₋₃ alkyl)NR⁹R¹⁰ and —OCF₃.

In some embodiments of Formula Ia, R⁷ is 1-3 substituents attached tothe aryl ring and each is independently selected from the groupconsisting of H, C₁₋₃ alkyl, —CF₃, halide, —CN, —OR⁸, —OH, —(C₁₋₃alkyl)OR⁸, —NR⁹R¹⁰, —(C₁₋₃ alkyl)NR⁹R¹⁰ and —OCF₃.

In some embodiments of Formula Ia, each R⁸ is selected from the groupconsisting of C₁₋₉ alkyl, -heteroarylR¹², -heterocyclylR¹³, -arylR¹⁴,carbocyclylR¹¹, —(C₁₋₃ alkyl)heteroarylR¹², —(C₁₋₃alkyl)heterocyclylR¹³, —(C₁₋₃ alkyl)arylR¹⁴ and —(C₁₋₃alkyl)carbocyclylR¹¹.

In some embodiments of Formula Ia, each R⁹ is selected from the groupconsisting of H, C₁₋₆ alkyl, -heteroarylR¹², -heterocyclylR¹³, -arylR¹⁴,carbocyclylR¹¹, —(C₁₋₃ alkyl)heteroarylR¹², —(C₁₋₃alkyl)heterocyclylR¹³, —(C₁₋₃ alkyl)arylR¹⁴ and —(C₁₋₃alkyl)carbocyclylR¹¹.

In some embodiments of Formula Ia, each R¹⁰ is selected from the groupconsisting of H and C₁₋₆ alkyl.

In some embodiments of Formula Ia, R⁹ and R¹⁰ are linked to form a fiveor six membered heterocyclyl ring.

In some embodiments of Formula Ia, R¹¹ is 1-3 substituents attached tothe carbocyclyl ring and each independently selected from the groupconsisting of H, C₁₋₃ alkyl, —CF₃, halide, —CN, —O(R¹⁰), —(C₁₋₃alkyl)OR¹⁰, —N(R¹⁰)₂, —(C₁₋₃ alkyl)N(R¹⁰)₂ and —OCF₃;

In some embodiments of Formula Ia, R¹² is 1-3 substituents attached tothe heteroaryl ring and each is independently selected from the groupconsisting of H, C₁₋₃ alkyl, —CF₃, halide, —CN, —O(R¹⁰), —(C₁₋₃alkyl)OR¹⁰, —N(R¹⁰)₂, —(C₁₋₃ alkyl)N(R¹⁰)₂ and —OCF₃;

In some embodiments of Formula Ia, R¹³ is 1-3 substituents attached tothe heterocyclyl ring and each is independently selected from the groupconsisting of H, C₁₋₃ alkyl, —CF₃, halide, —CN, —O(R¹⁰), —(C₁₋₃alkyl)OR¹⁰, —N(R¹⁰)₂, —(C₁₋₃ alkyl)N(R¹⁰)₂ and —OCF₃;

In some embodiments of Formula Ia, R¹⁴ is 1-3 substituents attached tothe aryl ring and each is independently selected from the groupconsisting of H, C₁₋₃ alkyl, —CF₃, halide, —CN, —O(R¹⁰), —(C₁₋₃alkyl)OR¹⁰, —N(R¹⁰)₂, —(C₁₋₃ alkyl)N(R¹⁰)₂ and —OCF₃;

In other embodiments of Formula Ia, there is the proviso that a compoundof Formula Ia is not a compound selected from the group consisting of:

In some embodiments of Formula I, R¹ is pyridineR³R⁴.

In some embodiments of Formulas I and/or Ia, R¹ is pyridin-3-ylR³R⁴.

In some embodiments of Formulas I and/or Ia, R³ and R⁴ are both H.

In some embodiments of Formulas I and/or Ia, R³ is —C₁₋₂ alkyl and R⁴ isH.

In some embodiments of Formulas I and/or Ia, R³ is methyl.

In some embodiments of Formulas I and/or Ia, R³ is ethyl.

In some embodiments of Formulas I and/or Ia, R³ is —CH₂NR⁹R¹⁰.

In some embodiments of Formula I, R⁴ is H.

In some embodiments of Formulas I and/or Ia, R⁹ is —C₁₋₂ alkyl; R¹⁰ is—(C₁₋₂ alkyl); and R⁴ is H.

In some embodiments of Formulas I and/or Ia, R⁴ and R⁹ are both H;

-   -   and R¹⁰ is selected from the group consisting of —C₁₋₂ alkyl,        —CH₂phenyl and —CH₂carbocyclyl.

In some embodiments of Formulas I and/or Ia, R⁹ is —CH₂cyclopropyl.

In some embodiments of Formulas I and/or Ia, R⁹ is —CH₂cyclobutyl.

In some embodiments of Formulas I and/or Ia, R⁹ is —CH₂cyclopentyl.

In some embodiments of Formulas I and/or Ia, R⁹ is —CH₂cyclohexyl.

In some embodiments of Formulas I and/or (Ia), R⁹ and R¹⁰ are linked toform a five or six membered heterocyclyl ring and R⁴ is H.

In some embodiments of Formulas I and/or Ia, R⁹ and R¹⁰ are linked toform a morpholine ring.

In some embodiments of Formulas I and/or Ia, R⁹ and R¹⁰ are linked toform a piperidine ring.

In some embodiments of Formulas I and/or Ia, R⁹ and R¹⁰ are linked toform a pyrrolidine ring.

In some embodiments of Formulas I and/or Ia, R⁹ and R¹⁰ are linked toform a piperazine ring.

In some embodiments of Formulas I and/or Ia, R³ is —NHC(═O)R⁸.

In some embodiments of Formulas I and/or Ia, R⁴ is H; and R⁸ is selectedfrom the group consisting of —C₁₋₅ alkyl, —CH₂phenyl, phenyl and-carbocyclyl.

In another aspect of embodiments of Formulas I and/or Ia, R⁸ is a —C₁₋₅alkyl. For example, the —C₁₋₅ alkyl can be selected from the groupconsisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, tert-butyl, n-pentyl, iso-pentyl and neo-pentyl. In certainembodiments, R⁸ is methyl. In another embodiment, R⁸ is ethyl. Inanother embodiment, R⁸ is n-propyl. In another embodiment, R⁸ isiso-propyl. In another embodiment, R⁸ is n-butyl. In another embodiment,R⁸ is iso-butyl. In another embodiment, R⁸ is sec-butyl. In anotherembodiment, R⁸ is tert-butyl. In another embodiment, R⁸ is n-pentyl. Inanother embodiment, R⁸ is iso-pentyl. In another embodiment, R⁸ isneo-pentyl.

In some embodiments of Formulas I and/or Ia, R⁸ is —CH₂phenyl.

In some embodiments of Formulas I and/or Ia, R⁸ is phenyl.

In some embodiments of Formulas I and/or Ia, R⁸ is a carbocyclyl. Forexample, the carbocyclyl can be selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certainembodiments, R⁸ is cyclopropyl. In another embodiment, R⁸ is cyclobutyl.In another embodiment, R⁸ is cyclopentyl. In another embodiment, R⁸ iscyclohexyl.

In some embodiments of Formulas I and/or Ia, R³ is —NR⁹R¹⁰.

In some embodiments of Formulas I and/or Ia, R³ is —NH₂ and R⁴ is H.

In some embodiments of Formulas I and/or Ia, R⁹ is —C₁₋₂ alkyl; R¹⁰ is—C₁₋₂ alkyl; and R⁴ is H.

In some embodiments of Formulas I and/or Ia, R⁹ is methyl and R¹⁰ ismethyl.

In some embodiments of Formulas I and/or Ia, R⁹ is methyl and R¹⁰ isethyl.

In some embodiments of Formulas I and/or Ia, R⁹ is ethyl and R¹⁰ isethyl.

In some embodiments of Formulas I and/or Ia, R⁴ and R⁹ are both H; andR¹⁰ is —C₁₋₄ alkyl.

In some embodiments of Formulas I and/or Ia, R¹⁰ is a —C₁₋₄ alkyl. Forexample, the —C₁₋₄ alkyl can be selected from the group consisting ofmethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl andtert-butyl. In certain embodiments, R¹⁰ is methyl. In anotherembodiment, R¹⁰ is ethyl. In another embodiment, R¹⁰ is n-propyl. Inanother embodiment, R¹⁰ is iso-propyl. In another embodiment, R¹⁰ isn-butyl. In another embodiment, R¹⁰ is iso-butyl. In another embodiment,R¹⁰ is sec-butyl. In another embodiment, R¹⁰ is tert-butyl.

In some embodiments of Formulas I and/or Ia, R² is H.

In some embodiments of Formulas I and/or Ia, R² is -heteroarylR⁵.

In some embodiments of Formulas I and/or Ia, R⁵ is H.

In some embodiments of Formulas I and/or Ia, R² is -pyridine.

In some embodiments of Formulas I and/or Ia, R² is -pyridin-2-yl.

In some embodiments of Formulas I and/or Ia, R² is -pyridin-3-yl.

In some embodiments of Formulas I and/or Ia, R² is -pyridin-4-yl.

In some embodiments of Formulas I and/or Ia, R² is thiophene.

In some embodiments of Formulas I and/or Ia, R² is furan.

In some embodiments of Formulas I and/or Ia, R² is -imidazolylR⁵; and R⁵is 1 substituent selected from the group consisting of H or —C₁₋₂ alkyl.

In some embodiments of Formulas I and/or Ia, R⁵ is methyl.

In some embodiments of Formulas I and/or Ia, R⁵ is ethyl.

In some embodiments of Formulas I and/or Ia, R² is a heterocyclyl. Forexample, the heterocyclyl can be selected from the group consisting ofmorpholinyl, piperazinyl, 1-methylpiperazinyl, piperidinyl andpyrrolidinyl. In certain embodiments, R² is piperidinyl. In anotherembodiment, R² is piperazinyl. In another embodiment, R² is1-methylpiperazinyl.

In some embodiments of Formulas I and/or Ia, R² is -piperazineR⁶; and R⁶is 1 substituent selected from the group consisting of H or —C₁₋₂ alkyl.

In some embodiments of Formulas I and/or Ia, R⁶ is methyl.

In some embodiments of Formulas I and/or Ia, R⁶ is ethyl.

In some embodiments of Formulas I and/or Ia, R² is -phenyllR⁷.

In some embodiments of Formulas I and/or Ia, R⁷ is 1 fluorine atom.

In some embodiments of Formulas I and/or Ia, R⁷ is 2 fluorine atoms.

In some embodiments of Formulas I and/or Ia, R¹ is pyridin-3-ylR³R⁴; R²is -phenyllR⁷; R³ is selected from the group consisting of H, —C₁₋₂alkyl, —CH₂NR⁹R¹⁰, —NR⁹R¹⁰ and —NHC(═O)R⁸; R⁴ is H; R⁷ is 1-2 fluorineatoms; R⁸ is selected from the group consisting of —C₁₋₅ alkyl,—CH₂phenyl, phenyl and -carbocyclyl; R⁹ is selected from the groupconsisting of —C₁₋₃ alkyl, —CH₂phenyl and —CH₂carbocyclyl; R¹⁰ is H or—C₁₋₂ alkyl; or R⁹ and R¹⁰ are optionally linked to form a piperidine orpyrrolidine ring.

In some embodiments of Formulas I and/or Ia, R¹ is pyridin-3-ylR³R⁴; R²is pyridine; R³ is selected from the group consisting of —C₁₋₂ alkyl,—CH₂NR⁹R¹⁰, —NR⁹R¹⁰ and —NHC(═O)R⁸; R⁴ is H; R⁸ is selected from thegroup consisting of —C₁₋₅ alkyl, —CH₂phenyl and -carbocyclyl; R⁹ isselected from the group consisting of H, —C₁₋₃ alkyl, —CH₂phenyl and—CH₂carbocyclyl; R¹⁰ is H or —C₁₋₂ alkyl; or R⁹ and R¹⁰ are optionallylinked to form a pyrrolidine ring.

In some embodiments of Formulas I and/or Ia, R¹ is pyridin-3-ylR³R⁴; R²is 1-methylpiperazinyl- or piperidinyl-; R³ is selected from the groupconsisting of H, —C₁₋₂ alkyl, —CH₂NR⁹R¹⁰, —NR⁹R¹⁰ and —NHC(═O)R⁸; R⁴ isH; R⁸ is selected from the group consisting of —C₁₋₅ alkyl, —CH₂phenyl,phenyl and -carbocyclyl; R⁹ is H or —C₁₋₂ alkyl; R¹⁰ is —C₁₋₃ alkyl; orR⁹ and R¹⁰ are optionally linked to form a piperidine or pyrrolidinering.

In some embodiments of Formulas I and/or Ia, R¹ is pyridin-3-ylR³R⁴; R²is selected from the group consisting of furan, thiophene and-imidazolylR⁵; R³ is selected from the group consisting of —CH₂NR⁹R¹⁰,—NR⁹R¹⁰ and —NHC(═O)R⁸; R⁴ is H; R⁵ is H or —C₁₋₂ alkyl; R⁸ is selectedfrom the group consisting of —C₁₋₅ alkyl, —CH₂phenyl and -carbocyclyl;R⁹ is selected from the group consisting of H, —C₁₋₃ alkyl and—CH₂phenyl; R¹⁰ is H or —C₁₋₂ alkyl; or R⁹ and R¹⁰ are optionally linkedto form a piperidine or pyrrolidine ring.

In some embodiments of Formulas I and/or Ia, R¹ is pyridin-3-ylR³R⁴; R²is H; R³ is selected from the group consisting of —C₁₋₂ alkyl,—CH₂NR⁹R¹⁰ and —NHC(═O)R⁸; R⁴ is H; R⁸ is selected from the groupconsisting of —C₁₋₅ alkyl, phenyl and -carbocyclyl; R⁹ is —CH₂phenyl;and R¹⁰ is H.

In some embodiments of Formulas I and/or Ia, R² is selected from thegroup consisting of: H,

In some embodiments of Formulas I and/or Ia, R is selected from thegroup consisting of:

Illustrative compounds of Formulas I and/or Ia are shown in Table 1.

TABLE 1 1

2

3

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5

6

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Administration and Pharmaceutical Compositions

Some embodiments include pharmaceutical compositions comprising: (a) atherapeutically effective amount of a compound provided herein, or itscorresponding enantiomer, diastereoisomer or tautomer, orpharmaceutically acceptable salt; and (b) a pharmaceutically acceptablecarrier.

The compounds provided herein may also be useful in combination(administered together or sequentially) with other known agents.

Non-limiting examples of diseases which can be treated with acombination of a compound of Formula (I) or (Ia) and other known agentsare colorectal cancer, ovarian cancer, diabetic retinopathy, pulmonaryfibrosis, and osteoarthritis.

In some embodiments, colorectal cancer can be treated with a combinationof a compound of either Formula (I) or (Ia) and one or more of thefollowing drugs: 5-Fluorouracil (5-FU), which can be administered withthe vitamin-like drug leucovorin (also called folinic acid);capecitabine (Xeloda®), irinotecan (Camptosar®), oxaliplatin(Eloxatin®). Examples of combinations of these drugs which could befurther combined with a compound of either Formula (I) or (Ia) areFOLFOX (5-FU, leucovorin, and oxaliplatin), FOLFIRI (5-FU, leucovorin,and irinotecan), FOLFOXIRI (leucovorin, 5-FU, oxaliplatin, andirinotecan) and CapeOx (Capecitabine and oxaliplatin). For rectalcancer, chemo with 5-FU or capecitabine combined with radiation may begiven before surgery (neoadjuvant treatment).

In some embodiments, ovarian cancer can be treated with a combination ofa compound of either Formula (I) or (Ia) and one or more of thefollowing drugs: Topotecan, Liposomal doxorubicin (Doxil®), Gemcitabine(Gemzar®), Cyclophosphamide (Cytoxan®), Vinorelbine (Navelbine®),Ifosfamide (Ifex®), Etoposide (VP-16), Altretamine (Hexalen®),Capecitabine (Xeloda®), Irinotecan (CPT-11, Camptosar®), Melphalan,Pemetrexed (Alimta®) and Albumin bound paclitaxel (nab-paclitaxel,Abraxane®). Examples of combinations of these drugs which could befurther combined with a compound of either Formula (I) or (Ia) are TIP(paclitaxel [Taxol], ifosfamide, and cisplatin), VeIP (vinblastine,ifosfamide, and cisplatin) and VIP (etoposide [VP-16], ifosfamide, andcisplatin).

In some embodiments, a compound of either Formula (I) or (Ia) can beused to treat cancer in combination with any of the following methods:(a) Hormone therapy such as aromatase inhibitors, LHRH [luteinizinghormone-releasing hormone] analogs and inhibitors, and others; (b)Ablation or embolization procedures such as radiofrequency ablation(RFA), ethanol (alcohol) ablation, microwave thermotherapy andcryosurgery (cryotherapy); (c) Chemotherapy using alkylating agents suchas cisplatin and carboplatin, oxaliplatin, mechlorethamine,cyclophosphamide, chlorambucil and ifosfamide; (d) Chemotherapy usinganti-metabolites such as azathioprine and mercaptopurine; (e)Chemotherapy using plant alkaloids and terpenoids such as vincaalkaloids (i.e. Vincristine, Vinblastine, Vinorelbine and Vindesine) andtaxanes; (f) Chemotherapy using podophyllotoxin, etoposide, teniposideand docetaxel; (g) Chemotherapy using topoisomerase inhibitors such asirinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, andteniposide; (h) Chemotherapy using cytotoxic antibiotics such asactinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin,idarubicin, epirubicin, bleomycin, plicamycin and mitomycin; (i)Chemotherapy using tyrosine-kinase inhibitors such as Imatinib mesylate(Gleevec®, also known as STI-571), Gefitinib (Iressa, also known asZD1839), Erlotinib (marketed as Tarceva®), Bortezomib (Velcade®),tamoxifen, tofacitinib, crizotinib, Bcl-2 inhibitors (e.g. obatoclax inclinical trials, ABT-263, and Gossypol), PARP inhibitors (e.g. Iniparib,Olaparib in clinical trials), PI3K inhibitors (eg. perifosine in a phaseIII trial), VEGF Receptor 2 inhibitors (e.g. Apatinib), AN-152,(AEZS-108), Braf inhibitors (e.g. vemurafenib, dabrafenib and LGX818),MEK inhibitors (e.g. trametinib and MEK162), CDK inhibitors, (e.g.PD-0332991), salinomycin and Sorafenib; (j) Chemotherapy usingmonoclonal antibodies such as Rituximab (marketed as MabThera® orRituxan®), Trastuzumab (Herceptin also known as ErbB2), Cetuximab(marketed as Erbitux®), and Bevacizumab (marketed as Avastin®); and (k)radiation therapy.

In some embodiments, diabetic retinopathy can be treated with acombination of a compound of either Formula (I) or (Ia) and one or moreof the following natural supplements: Bilberry, Butcher's broom, Ginkgo,Grape seed extract, and Pycnogenol (Pine bark).

In some embodiments, a compound of either Formula (I) or (Ia) can beused to treat pulmonary fibrosis in combination with any of thefollowing methods: oxygen therapy, pulmonary rehabilitation, andsurgery.

In some embodiments, a compound of either Formula (I) or (Ia) can beused to treat osteoarthritis in combination with any of the followingmethods: (a) Nonsteroidal anti-inflammatory drugs (NSAIDs) such asibuprofen, naproxen and acetaminophen; (b) physical therapy; (c)injections of corticosteroid medications; and (d) injections ofhyaluronic acid derivatives (e.g. Hyalgan, Synvisc).

Administration of the compounds disclosed herein or the pharmaceuticallyacceptable salts thereof can be via any of the accepted modes ofadministration, including, but not limited to, orally, subcutaneously,intravenously, intranasally, topically, transdermally,intraperitoneally, intramuscularly, intrapulmonarilly, vaginally,rectally, ontologically, neuro-otologically, intraocularly,subconjuctivally, via anterior eye chamber injection, intravitreally,intraperitoneally, intrathecally, intracystically, intrapleurally, viawound irrigation, intrabuccally, intra-abdominally, intra-articularly,intra-aurally, intrabronchially, intracapsularly, intrameningeally, viainhalation, via endotracheal or endobronchial instillation, via directinstillation into pulmonary cavities, intraspinally, intrasynovially,intrathoracically, via thoracostomy irrigation, epidurally,intratympanically, intracisternally, intravascularly,intraventricularly, intraosseously, via irrigation of infected bone, orvia application as part of any admixture with a prosthetic devices. Insome embodiments, the administration method includes oral or parenteraladministration.

Compounds provided herein intended for pharmaceutical use may beadministered as crystalline or amorphous products. Pharmaceuticallyacceptable compositions may be solid, semi-solid, liquid, solutions,colloidal, liposomes, emulsions, suspensions, complexes, coacervates,and aerosols. Dosage forms, such as, e.g., tablets, capsules, powders,liquids, suspensions, suppositories, aerosols, implants, controlledrelease or the like are provided herein. They may be obtained, forexample, as solid plugs, powders, or films by methods such asprecipitation, crystallization, milling, grinding, supercritical fluidprocessing, coacervation, complex coacervation, encapsulation,emulsification, complexation, freeze drying, spray drying, orevaporative drying. Microwave or radio frequency drying may be used forthis purpose. The compounds can also be administered in sustained orcontrolled release dosage forms, including depot injections, osmoticpumps, pills (tablets and or capsules), transdermal (includingelectrotransport) patches, implants, and the like, for prolonged and/ortimed, pulsed administration at a predetermined rate.

The compounds can be administered either alone or in combination with aconventional pharmaceutical carrier, excipient or the like.Pharmaceutically acceptable excipients include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifyingdrug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol1000 succinate, surfactants used in pharmaceutical dosage forms such asTweens, poloxamers or other similar polymeric delivery matrices, serumproteins, such as human serum albumin, buffer substances such asphosphates, tris, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethyl cellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, andwool fat. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemicallymodified derivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives canalso be used to enhance delivery of compounds described herein. Dosageforms or compositions containing a compound as described herein in therange of 0.005% to 100% with the balance made up from non-toxic carriermay be prepared. The contemplated compositions may contain 0.001%-100%of a compound provided herein, in one embodiment 0.1-95%, in anotherembodiment 75-85%, in a further embodiment 20-80%. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see Remington: The Science andPractice of Pharmacy, 22^(nd) Edition (Pharmaceutical Press, London, UK. 2012).

In one embodiment, the compositions will take the form of a unit dosageform such as a pill or tablet and thus the composition may contain,along with a compound provided herein, a diluent such as lactose,sucrose, dicalcium phosphate, or the like; a lubricant such as magnesiumstearate or the like; and a binder such as starch, gum acacia,polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or thelike. In another solid dosage form, a powder, marume, solution orsuspension (e.g., in propylene carbonate, vegetable oils, PEG's,poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin orcellulose base capsule). Unit dosage forms in which one or morecompounds provided herein or additional active agents are physicallyseparated are also contemplated; e.g., capsules with granules (ortablets in a capsule) of each drug; two-layer tablets; two-compartmentgel caps, etc. Enteric coated or delayed release oral dosage forms arealso contemplated.

Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, etc. a compound provided herein andoptional pharmaceutical adjuvants in a carrier (e.g., water, saline,aqueous dextrose, glycerol, glycols, ethanol or the like) to form asolution, colloid, liposome, emulsion, complexes, coacervate orsuspension. If desired, the pharmaceutical composition can also containminor amounts of nontoxic auxiliary substances such as wetting agents,emulsifying agents, co-solvents, solubilizing agents, pH bufferingagents and the like (e.g., sodium acetate, sodium citrate, cyclodextrinederivatives, sorbitan monolaurate, triethanolamine acetate,triethanolamine oleate, and the like).

In some embodiments, the unit dosage of compounds of Formulas (I) and/or(Ia) is about 0.25 mg/Kg to about 50 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formulas (I) and/or(Ia) is about 0.25 mg/Kg to about 20 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formulas (I) and/or(Ia) is about 0.50 mg/Kg to about 19 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formulas (I) and/or(Ia) is about 0.75 mg/Kg to about 18 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formulas (I) and/or(Ia) is about 1.0 mg/Kg to about 17 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formulas (I) and/or(Ia) is about 1.25 mg/Kg to about 16 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formulas (I) and/or(Ia) is about 1.50 mg/Kg to about 15 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formulas (I) and/or(Ia) is about 1.75 mg/Kg to about 14 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formulas (I) and/or(Ia) is about 2.0 mg/Kg to about 13 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formulas (I) and/or(Ia) is about 3.0 mg/Kg to about 12 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formulas (I) and/or(Ia) is about 4.0 mg/Kg to about 11 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formulas (I) and/or(Ia) is about 5.0 mg/Kg to about 10 mg/Kg in humans.

In some embodiments, the compositions are provided in unit dosage formssuitable for single administration.

In some embodiments, the compositions are provided in unit dosage formssuitable for twice a day administration.

In some embodiments, the compositions are provided in unit dosage formssuitable for three times a day administration.

Injectables can be prepared in conventional forms, either as liquidsolutions, colloid, liposomes, complexes, coacervate or suspensions, asemulsions, or in solid forms suitable for reconstitution in liquid priorto injection. The percentage of a compound provided herein contained insuch parenteral compositions is highly dependent on the specific naturethereof, as well as the activity of the compound and the needs of thepatient. However, percentages of active ingredient of 0.01% to 10% insolution are employable, and could be higher if the composition is asolid or suspension, which could be subsequently diluted to the abovepercentages.

In some embodiments, the composition will comprise about 0.1-10% of theactive agent in solution.

In some embodiments, the composition will comprise about 0.1-5% of theactive agent in solution.

In some embodiments, the composition will comprise about 0.1-4% of theactive agent in solution.

In some embodiments, the composition will comprise about 0.15-3% of theactive agent in solution.

In some embodiments, the composition will comprise about 0.2-2% of theactive agent in solution.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1-96 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1-72 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1-48 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1-24 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1-12 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1-6 hours.

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 5 mg/m² to about 300mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 5 mg/m² to about 200mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 5 mg/m² to about 100mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 10 mg/m² to about 50mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 50 mg/m² to about 200mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 75 mg/m² to about 175mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 100 mg/m² to about 150mg/m².

It is to be noted that concentrations and dosage values may also varydepending on the specific compound and the severity of the condition tobe alleviated. It is to be further understood that for any particularpatient, specific dosage regimens should be adjusted over time accordingto the individual need and the professional judgment of the personadministering or supervising the administration of the compositions, andthat the concentration ranges set forth herein are exemplary only andare not intended to limit the scope or practice of the claimedcompositions.

In one preferred embodiment, the compositions can be administered to therespiratory tract (including nasal and pulmonary) e.g., through anebulizer, metered-dose inhalers, atomizer, mister, aerosol, dry powderinhaler, insufflator, liquid instillation or other suitable device ortechnique.

In some embodiments, aerosols intended for delivery to the nasal mucosaare provided for inhalation through the nose. For optimal delivery tothe nasal cavities, inhaled particle sizes of about 5 to about 100microns are useful, with particle sizes of about 10 to about 60 micronsbeing preferred. For nasal delivery, a larger inhaled particle size maybe desired to maximize impaction on the nasal mucosa and to minimize orprevent pulmonary deposition of the administered formulation. In someembodiments, aerosols intended for delivery to the lung are provided forinhalation through the nose or the mouth. For delivery to the lung,inhaled aerodynamic particle sizes of about less than 10 μm are useful(e.g., about 1 to about 10 microns). Inhaled particles may be defined asliquid droplets containing dissolved drug, liquid droplets containingsuspended drug particles (in cases where the drug is insoluble in thesuspending medium), dry particles of pure drug substance, drug substanceincorporated with excipients, liposomes, emulsions, colloidal systems,coacervates, aggregates of drug nanoparticles, or dry particles of adiluent which contain embedded drug nanoparticles.

In some embodiments, compounds of Formulas (I) and/or (Ia) disclosedherein intended for respiratory delivery (either systemic or local) canbe administered as aqueous formulations, as non-aqueous solutions orsuspensions, as suspensions or solutions in halogenated hydrocarbonpropellants with or without alcohol, as a colloidal system, asemulsions, coacervates, or as dry powders. Aqueous formulations may beaerosolized by liquid nebulizers employing either hydraulic orultrasonic atomization or by modified micropump systems (like the softmist inhalers, the Aerodose® or the AERx® systems). Propellant-basedsystems may use suitable pressurized metered-dose inhalers (pMDIs). Drypowders may use dry powder inhaler devices (DPIs), which are capable ofdispersing the drug substance effectively. A desired particle size anddistribution may be obtained by choosing an appropriate device.

In some embodiments, the compositions of Formulas (I) and/or (Ia)disclosed herein can be administered to the ear by various methods. Forexample, a round window catheter (e.g., U.S. Pat. Nos. 6,440,102 and6,648,873) can be used.

Alternatively, formulations can be incorporated into a wick for usebetween the outer and middle ear (e.g., U.S. Pat. No. 6,120,484) orabsorbed to collagen sponge or other solid support (e.g., U.S. Pat. No.4,164,559).

If desired, formulations of the disclosure can be incorporated into agel formulation (e.g., U.S. Pat. Nos. 4,474,752 and 6,911,211).

In some embodiments, compounds of Formulas (I) and/or (Ia) disclosedherein intended for delivery to the ear can be administered via animplanted pump and delivery system through a needle directly into themiddle or inner ear (cochlea) or through a cochlear implant styletelectrode channel or alternative prepared drug delivery channel such asbut not limited to a needle through temporal bone into the cochlea.

Other options include delivery via a pump through a thin film coatedonto a multichannel electrode or electrode with a specially imbeddeddrug delivery channel (pathways) carved into the thin film for thispurpose. In other embodiments, the acidic or basic solid gacyclidine canbe delivered from the reservoir of an external or internal implantedpumping system.

Formulations of the disclosure also can be administered to the ear byintratympanic injection into the middle ear, inner ear, or cochlea(e.g., U.S. Pat. No. 6,377,849 and Ser. No. 11/337,815).

Intratympanic injection of therapeutic agents is the technique ofinjecting a therapeutic agent behind the tympanic membrane into themiddle and/or inner ear. In one embodiment, the formulations describedherein are administered directly onto the round window membrane viatranstympanic injection. In another embodiment, the ion channelmodulating agent auris-acceptable formulations described herein areadministered onto the round window membrane via a non-transtympanicapproach to the inner ear. In additional embodiments, the formulationdescribed herein is administered onto the round window membrane via asurgical approach to the round window membrane comprising modificationof the crista fenestrae cochleae.

In some embodiments, the compounds of Formulas (I) and/or (Ia) areformulated in rectal compositions such as enemas, rectal gels, rectalfoams, rectal aerosols, suppositories, jelly suppositories, or retentionenemas, containing conventional suppository bases such as cocoa butteror other glycerides, as well as synthetic polymers such aspolyvinylpyrrolidone, PEG (like PEG ointments), and the like.

Suppositories for rectal administration of the drug (either as asolution, colloid, suspension or a complex) can be prepared by mixing acompound provided herein with a suitable non-irritating excipient thatis solid at ordinary temperatures but liquid at the rectal temperatureand will therefore melt or erode/dissolve in the rectum and release thecompound. Such materials include cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, poloxamers, mixtures of polyethyleneglycols of various molecular weights and fatty acid esters ofpolyethylene glycol. In suppository forms of the compositions, alow-melting wax such as, but not limited to, a mixture of fatty acidglycerides, optionally in combination with cocoa butter, is firstmelted.

Solid compositions can be provided in various different types of dosageforms, depending on the physicochemical properties of the compoundprovided herein, the desired dissolution rate, cost considerations, andother criteria. In one of the embodiments, the solid composition is asingle unit. This implies that one unit dose of the compound iscomprised in a single, physically shaped solid form or article. In otherwords, the solid composition is coherent, which is in contrast to amultiple unit dosage form, in which the units are incoherent.

Examples of single units which may be used as dosage forms for the solidcomposition include tablets, such as compressed tablets, film-likeunits, foil-like units, wafers, lyophilized matrix units, and the like.In one embodiment, the solid composition is a highly porous lyophilizedform. Such lyophilizates, sometimes also called wafers or lyophilizedtablets, are particularly useful for their rapid disintegration, whichalso enables the rapid dissolution of the compound.

On the other hand, for some applications the solid composition may alsobe formed as a multiple unit dosage form as defined above. Examples ofmultiple units are powders, granules, microparticles, pellets,mini-tablets, beads, lyophilized powders, and the like. In oneembodiment, the solid composition is a lyophilized powder. Such adispersed lyophilized system comprises a multitude of powder particles,and due to the lyophilization process used in the formation of thepowder, each particle has an irregular, porous microstructure throughwhich the powder is capable of absorbing water very rapidly, resultingin quick dissolution. Effervescent compositions are also contemplated toaid the quick dispersion and absorption of the compound.

Another type of multiparticulate system which is also capable ofachieving rapid drug dissolution is that of powders, granules, orpellets from water-soluble excipients which are coated with a compoundprovided herein so that the compound is located at the outer surface ofthe individual particles. In this type of system, the water-soluble lowmolecular weight excipient may be useful for preparing the cores of suchcoated particles, which can be subsequently coated with a coatingcomposition comprising the compound and, for example, one or moreadditional excipients, such as a binder, a pore former, a saccharide, asugar alcohol, a film-forming polymer, a plasticizer, or otherexcipients used in pharmaceutical coating compositions.

Also provided herein are kits. Typically, a kit includes one or morecompounds or compositions as described herein. In certain embodiments, akit can include one or more delivery systems, e.g., for delivering oradministering a compound as provided herein, and directions for use ofthe kit (e.g., instructions for treating a patient). In anotherembodiment, the kit can include a compound or composition as describedherein and a label that indicates that the contents are to beadministered to a patient with cancer. In another embodiment, the kitcan include a compound or composition as described herein and a labelthat indicates that the contents are to be administered to a patientwith one or more of hepatocellular carcinoma, colon cancer, leukemia,lymphoma, sarcoma, ovarian cancer, diabetic retinopathy, pulmonaryfibrosis, rheumatoid arthritis, sepsis, anklyosing spondylitism,psoriasis, scleroderma, mycotic and viral infections, bone and cartilagediseases, Alzheimer's disease, lung disease, osteoarthritis, articularcartilage (chondral) defects, degenerative disc disease (orintervertebral disc degeneration), polyposis coli, bone density andvascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG),familial exudative vitreoretinopathy, retinal angiogenesis, earlycoronary disease, tetra-amelia, Müllerian-duct regression andvirilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome,Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia,focal dermal hypoplasia, autosomal recessive anonychia, neural tubedefects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICFsyndrome, Angelman's syndrome, Prader-Willi syndrome, Beckwith-WiedemannSyndrome, Norrie disease, and Rett syndrome.

Methods of Treatment

The compounds and compositions provided herein can be used as inhibitorsand/or modulators of one or more components of the Wnt pathway, whichmay include one or more Wnt proteins, and thus can be used to treat avariety of disorders and diseases in which aberrant Wnt signaling isimplicated, such as cancer and other diseases associated with abnormalangiogenesis, cellular proliferation, and cell cycling. Accordingly, thecompounds and compositions provided herein can be used to treat cancer,to reduce or inhibit angiogenesis, to reduce or inhibit cellularproliferation, to correct a genetic disorder, and/or to treat aneurological condition/disorder/disease due to mutations ordysregulation of the Wnt pathway and/or of one or more of Wnt signalingcomponents. Non-limiting examples of diseases which can be treated withthe compounds and compositions provided herein include a variety ofcancers, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis,sepsis, anklyosing spondylitism, psoriasis, scleroderma, mycotic andviral infections, bone and cartilage diseases, neurologicalconditions/diseases such as Alzheimer's disease, amyotrophic lateralsclerosis (ALS), motor neurone disease, multiple sclerosis or autism,lung disease, osteoarthritis, articular cartilage (chondral) defects,degenerative disc disease (or intervertebral disc degeneration),polyposis coli, bone density and vascular defects in the eye(Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudativevitreoretinopathy, retinal angiogenesis, early coronary disease,tetra-amelia, Müllerian-duct regression and virilization, SERKALsyndrome, type II diabetes, Fuhrmann syndrome,Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia,focal dermal hypoplasia, autosomal recessive anonychia, neural tubedefects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICFsyndrome, Angelman's syndrome, Prader-Willi syndrome, Beckwith-WiedemannSyndrome, Norrie disease, and Rett syndrome.

With respect to cancer, the Wnt pathway is known to be constitutivelyactivated in a variety of cancers including, for example, colon cancer,hepatocellular carcinoma, lung cancer, ovarian cancer, prostate cancer,pancreatic cancer and leukemias such as CML, CLL and T-ALL. Accordingly,the compounds and compositions described herein may be used to treatthese cancers in which the Wnt pathway is constitutively activated. Incertain embodiments, the cancer is chosen from hepatocellular carcinoma,colon cancer, leukemia, lymphoma, sarcoma and ovarian cancer.

Other cancers can also be treated with the compounds and compositionsdescribed herein.

More particularly, cancers that may be treated by the compound,compositions and methods described herein include, but are not limitedto, the following:

1) Breast cancers, including, for example ER⁺ breast cancer, ER⁻ breastcancer, her2⁻ breast cancer, her2⁺ breast cancer, stromal tumors such asfibroadenomas, phyllodes tumors, and sarcomas, and epithelial tumorssuch as large duct papillomas; carcinomas of the breast including insitu (noninvasive) carcinoma that includes ductal carcinoma in situ(including Paget's disease) and lobular carcinoma in situ, and invasive(infiltrating) carcinoma including, but not limited to, invasive ductalcarcinoma, invasive lobular carcinoma, medullary carcinoma, colloid(mucinous) carcinoma, tubular carcinoma, and invasive papillarycarcinoma; and miscellaneous malignant neoplasms. Further examples ofbreast cancers can include luminal A, luminal B, basal A, basal B, andtriple negative breast cancer, which is estrogen receptor negative(ER⁻), progesterone receptor negative, and her2 negative (her2⁻). Insome embodiments, the breast cancer may have a high risk Oncotype score.

2) Cardiac cancers, including, for example sarcoma, e.g., angiosarcoma,fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma;fibroma; lipoma and teratoma.

3) Lung cancers, including, for example, bronchogenic carcinoma, e.g.,squamous cell, undifferentiated small cell, undifferentiated large cell,and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchialadenoma; sarcoma; lymphoma; chondromatous hamartoma; and mesothelioma.

4) Gastrointestinal cancer, including, for example, cancers of theesophagus, e.g., squamous cell carcinoma, adenocarcinoma,leiomyosarcoma, and lymphoma; cancers of the stomach, e.g., carcinoma,lymphoma, and leiomyosarcoma; cancers of the pancreas, e.g., ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,and vipoma; cancers of the small bowel, e.g., adenocarcinoma, lymphoma,carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma,neurofibroma, and fibroma; cancers of the large bowel, e.g.,adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, andleiomyoma.

5) Genitourinary tract cancers, including, for example, cancers of thekidney, e.g., adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma,and leukemia; cancers of the bladder and urethra, e.g., squamous cellcarcinoma, transitional cell carcinoma, and adenocarcinoma; cancers ofthe prostate, e.g., adenocarcinoma, and sarcoma; cancer of the testis,e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, and lipoma.

6) Liver cancers, including, for example, hepatoma, e.g., hepatocellularcarcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma;hepatocellular adenoma; and hemangioma.

7) Bone cancers, including, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochrondroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma and giant celltumors.

8) Nervous system cancers, including, for example, cancers of the skull,e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans;cancers of the meninges, e.g., meningioma, meningiosarcoma, andgliomatosis; cancers of the brain, e.g., astrocytoma, medulloblastoma,glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors;and cancers of the spinal cord, e.g., neurofibroma, meningioma, glioma,and sarcoma.

9) Gynecological cancers, including, for example, cancers of the uterus,e.g., endometrial carcinoma; cancers of the cervix, e.g., cervicalcarcinoma, and pre tumor cervical dysplasia; cancers of the ovaries,e.g., ovarian carcinoma, including serous cystadenocarcinoma, mucinouscystadenocarcinoma, unclassified carcinoma, granulosa theca cell tumors,Sertoli Leydig cell tumors, dysgerminoma, and malignant teratoma;cancers of the vulva, e.g., squamous cell carcinoma, intraepithelialcarcinoma, adenocarcinoma, fibrosarcoma, and melanoma; cancers of thevagina, e.g., clear cell carcinoma, squamous cell carcinoma, botryoidsarcoma, and embryonal rhabdomyosarcoma; and cancers of the fallopiantubes, e.g., carcinoma.

10) Hematologic cancers, including, for example, cancers of the blood,e.g., acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, and myelodysplastic syndrome, Hodgkin'slymphoma, non-Hodgkin's lymphoma (malignant lymphoma) and Waldenstrom'smacroglobulinemia.

11) Skin cancers and skin disorders, including, for example, malignantmelanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi'ssarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma,keloids, and scleroderma.

12) Adrenal gland cancers, including, for example, neuroblastoma.

Cancers may be solid tumors that may or may not be metastatic. Cancersmay also occur, as in leukemia, as a diffuse tissue. Thus, the term“tumor cell,” as provided herein, includes a cell afflicted by any oneof the above identified disorders.

A method of treating cancer using a compound or composition as describedherein may be combined with existing methods of treating cancers, forexample by chemotherapy, irradiation, or surgery (e.g., oophorectomy).In some embodiments, a compound or composition can be administeredbefore, during, or after another anticancer agent or treatment.

The compounds and compositions described herein can be used asanti-angiogenesis agents and as agents for modulating and/or inhibitingthe activity of protein kinases, thus providing treatments for cancerand other diseases associated with cellular proliferation mediated byprotein kinases. Accordingly, provided herein is a method of treatingcancer or preventing or reducing angiogenesis through kinase inhibition.

In addition, and including treatment of cancer, the compounds andcompositions described herein can function as cell-cycle control agentsfor treating proliferative disorders in a patient. Disorders associatedwith excessive proliferation include, for example, cancers, scleroderma,immunological disorders involving undesired proliferation of leukocytes,and restenosis and other smooth muscle disorders. Furthermore, suchcompounds may be used to prevent de-differentiation of post-mitotictissue and/or cells.

Diseases or disorders associated with uncontrolled or abnormal cellularproliferation include, but are not limited to, the following:

-   -   a variety of cancers, including, but not limited to, carcinoma,        hematopoietic tumors of lymphoid lineage, hematopoietic tumors        of myeloid lineage, tumors of mesenchymal origin, tumors of the        central and peripheral nervous system and other tumors including        melanoma, seminoma, and Kaposi's sarcoma.    -   a disease process which features abnormal cellular        proliferation, e.g., benign prostatic hyperplasia, familial        adenomatosis polyposis, neurofibromatosis, atherosclerosis,        arthritis, glomerulonephritis, restenosis following angioplasty        or vascular surgery, inflammatory bowel disease, transplantation        rejection, endotoxic shock, and fungal infections. Fibrotic        disorders such as skin fibrosis; scleroderma; progressive        systemic fibrosis; lung fibrosis; muscle fibrosis; kidney        fibrosis; glomerulosclerosis; glomerulonephritis; hypertrophic        scar formation; uterine fibrosis; renal fibrosis; cirrhosis of        the liver, liver fibrosis; adhesions, such as those occurring in        the abdomen, pelvis, spine or tendons; chronic obstructive        pulmonary disease; fibrosis following myocardial infarction;        pulmonary fibrosis; fibrosis and scarring associated with        diffuse/interstitial lung disease; central nervous system        fibrosis, such as fibrosis following stroke; fibrosis associated        with neuro-degenerative disorders such as Alzheimer's Disease or        multiple sclerosis; fibrosis associated with proliferative        vitreoretinopathy (PVR); restenosis; endometriosis; ischemic        disease and radiation fibrosis.    -   defective apoptosis-associated conditions, such as cancers        (including but not limited to those types mentioned herein),        viral infections (including but not limited to herpesvirus,        poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus),        prevention of AIDS development in HIV-infected individuals,        autoimmune diseases (including but not limited to systemic lupus        erythematosus, rheumatoid arthritis, sepsis, anklyosing        spondylitism, psoriasis, scleroderma, autoimmune mediated        glomerulonephritis, inflammatory bowel disease and autoimmune        diabetes mellitus), neuro-degenerative disorders (including but        not limited to Alzheimer's disease, lung disease, amyotrophic        lateral sclerosis, retinitis pigmentosa, Parkinson's disease,        AIDS-related dementia, spinal muscular atrophy and cerebellar        degeneration), myelodysplastic syndromes, aplastic anemia,        ischemic injury associated with myocardial infarctions, stroke        and reperfusion injury, arrhythmia, atherosclerosis,        toxin-induced or alcohol related liver diseases, hematological        diseases (including but not limited to chronic anemia and        aplastic anemia), degenerative diseases of the musculoskeletal        system (including but not limited to osteroporosis and        arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis,        multiple sclerosis, kidney diseases and cancer pain.    -   genetic diseases due to mutations in Wnt signaling components,        such as polyposis coli, bone density and vascular defects in the        eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial        exudative vitreoretinopathy, retinal angiogenesis, early        coronary disease, tetra-amelia, Müllerian-duct regression and        virilization, SERKAL syndrome, type II diabetes, Fuhrmann        syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,        odonto-onycho-dermal dysplasia, obesity, split-hand/foot        malformation, caudal duplication, tooth agenesis, Wilms tumor,        skeletal dysplasia, focal dermal hypoplasia, autosomal recessive        anonychia, neural tube defects, alpha-thalassemia (ATRX)        syndrome, fragile X syndrome, ICF syndrome, Angelman's syndrome,        Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie        disease and Rett syndrome.

Furthermore, the compounds and compositions described herein can be usedto treat neurological conditions, disorders and/or diseases caused bydysfunction in the Wnt signaling pathway. Non-limiting examples ofneurological conditions/disorders/diseases which can be treated with thecompounds and compositions provided herein include Alzheimer's disease,aphasia, apraxia, arachnoiditis, ataxia telangiectasia, attentiondeficit hyperactivity disorder, auditory processing disorder, autism,alcoholism, Bell's palsy, bipolar disorder, brachial plexus injury,Canavan disease, carpal tunnel syndrome, causalgia, central painsyndrome, central pontine myelinolysis, centronuclear myopathy, cephalicdisorder, cerebral aneurysm, cerebral arteriosclerosis, cerebralatrophy, cerebral gigantism, cerebral palsy, cerebral vasculitis,cervical spinal stenosis, Charcot-Marie-Tooth disease, Chiarimalformation, chronic fatigue syndrome, chronic inflammatorydemyelinating polyneuropathy (CIDP), chronic pain, Coffin-Lowrysyndrome, complex regional pain syndrome, compression neuropathy,congenital facial diplegia, corticobasal degeneration, cranialarteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulativetrauma disorder, Cushing's syndrome, cytomegalic inclusion body disease(CIBD), Dandy-Walker syndrome, Dawson disease, De Morsier's syndrome,Dejerine-Klumpke palsy, Dejerine-Sottas disease, delayed sleep phasesyndrome, dementia, dermatomyositis, developmental dyspraxia, diabeticneuropathy, diffuse sclerosis, Dravet syndrome, dysautonomia,dyscalculia, dysgraphia, dyslexia, dystonia, empty sella syndrome,encephalitis, encephalocele, encephalotrigeminal angiomatosis,encopresis, epilepsy, Erb's palsy, erythromelalgia, essential tremor,Fabry's disease, Fahr's syndrome, familial spastic paralysis, febrileseizure, Fisher syndrome, Friedreich's ataxia, fibromyalgia, Foville'ssyndrome, Gaucher's disease, Gerstmann's syndrome, giant cell arteritis,giant cell inclusion disease, globoid cell leukodystrophy, gray matterheterotopia, Guillain-Barre syndrome, HTLV-1 associated myelopathy,Hallervorden-Spatz disease, hemifacial spasm, hereditary spasticparaplegia, heredopathia atactica polyneuritiformis, herpes zosteroticus, herpes zoster, Hirayama syndrome, holoprosencephaly,Huntington's disease, hydranencephaly, hydrocephalus, hypercortisolism,hypoxia, immune-mediated encephalomyelitis, inclusion body myositis,incontinentia pigmenti, infantile phytanic acid storage disease,infantile Refsum disease, infantile spasms, inflammatory myopathy,intracranial cyst, intracranial hypertension, Joubert syndrome, Karaksyndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsbourne syndrome,Klippel Feil syndrome, Krabbe disease, Kugelberg-Welander disease, kuru,Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffnersyndrome, lateral medullary (Wallenberg) syndrome, Leigh's disease,Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, Lewy bodydementia, lissencephaly, locked-in syndrome, Lou Gehrig's disease,lumbar disc disease, lumbar spinal stenosis, Lyme disease,Machado-Joseph disease (Spinocerebellar ataxia type 3), macrencephaly,macropsia, megalencephaly, Melkersson-Rosenthal syndrome, Menieresdisease, meningitis, Menkes disease, etachromatic leukodystrophy,microcephaly, micropsia, Miller Fisher syndrome, misophonia,mitochondrial myopathy, Mobius syndrome, monomelic amyotrophy, motorneurone disease, motor skills disorder, Moyamoya disease,mucopolysaccharidoses, multi-infarct dementia, multifocal motorneuropathy, multiple sclerosis, multiple system atrophy, musculardystrophy, myalgic encephalomyelitis, myasthenia gravis, myelinoclasticdiffuse sclerosis, myoclonic Encephalopathy of infants, myoclonus,myopathy, myotubular myopathy, myotonia congenital, narcolepsy,neurofibromatosis, neuroleptic malignant syndrome, lupus erythematosus,neuromyotonia, neuronal ceroid lipofuscinosis, Niemann-Pick disease,O'Sullivan-McLeod syndrome, occipital Neuralgia, occult SpinalDysraphism Sequence, Ohtahara syndrome, olivopontocerebellar atrophy,opsoclonus myoclonus syndrome, optic neuritis, orthostatic hypotension,palinopsia, paresthesia, Parkinson's disease, paramyotonia Congenita,paraneoplastic diseases, paroxysmal attacks, Parry-Romberg syndrome,Pelizaeus-Merzbacher disease, periodic paralyses, peripheral neuropathy,photic sneeze reflex, phytanic acid storage disease, Pick's disease,polymicrogyria (PMG), polymyositis, porencephaly, post-polio syndrome,postherpetic neuralgia (PHN), postural hypotension, Prader-Willisyndrome, primary lateral sclerosis, prion diseases, progressivehemifacial atrophy, progressive multifocal leukoencephalopathy,progressive supranuclear palsy, pseudotumor cerebri, Ramsay Huntsyndrome type I, Ramsay Hunt syndrome type II, Ramsay Hunt syndrome typeIII, Rasmussen's encephalitis, reflex neurovascular dystrophy, Refsumdisease, restless legs syndrome, retrovirus-associated myelopathy, Rettsyndrome, Reye's syndrome, rhythmic movement disorder, Romberg syndrome,Saint Vitus dance, Sandhoff disease, schizophrenia, Schilder's disease,schizencephaly, sensory integration dysfunction, septo-optic dysplasia,Shy-Drager syndrome, Sjögren's syndrome, snatiation, Sotos syndrome,spasticity, spina bifida, spinal cord tumors, spinal muscular atrophy,spinocerebellar ataxia, Steele-Richardson-Olszewski syndrome,Stiff-person syndrome, stroke, Sturge-Weber syndrome, subacutesclerosing panencephalitis, subcortical arteriosclerotic encephalopathy,superficial siderosis, Sydenham's chorea, syncope, synesthesia,syringomyelia, tarsal tunnel syndrome, tardive dyskinesia, tardivedysphrenia, Tarlov cyst, Tay-Sachs disease, temporal arteritis, tetanus,tethered spinal cord syndrome, Thomsen disease, thoracic outletsyndrome, tic douloureux, Todd's paralysis, Tourette syndrome, toxicencephalopathy, transient ischemic attack, transmissible spongiformencephalopathies, transverse myelitis, tremor, trigeminal neuralgia,tropical spastic paraparesis, trypanosomiasis, tuberous sclerosis,ubisiosis, Von Hippel-Lindau disease (VHL), Viliuisk Encephalomyelitis(VE), Wallenberg's syndrome, Werdnig, Hoffman disease, west syndrome,Williams syndrome, Wilson's disease, and Zellweger syndrome.

The compounds and compositions may also be useful in the inhibition ofthe development of invasive cancer, tumor angiogenesis and metastasis.

In some embodiments, the disclosure provides a method for treating adisease or disorder associated with aberrant cellular proliferation byadministering to a patient in need of such treatment an effective amountof one or more of the compounds of Formulas (I) and/or (Ia), incombination (simultaneously or sequentially) with at least one otheragent.

In some embodiments, the pharmaceutical composition comprises atherapeutically effective amount of a compound of Formulas (I) and/or(Ia), or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient.

In some embodiments, the method of treating a disorder or disease inwhich aberrant Wnt signaling is implicated in a patient is providedherein, the method comprises administering to the patient atherapeutically effective amount of a compound of Formulas (I) and/or(Ia), or a pharmaceutically acceptable salt thereof.

In some embodiments, the disorder or disease is cancer.

In some embodiments, the disorder or disease is diabetic retinopathy.

In some embodiments, the disorder or disease is pulmonary fibrosis.

In some embodiments, the disorder or disease is rheumatoid arthritis.

In some embodiments, the disorder or disease is scleroderma.

In some embodiments, the disorder or disease is a mycotic or viralinfection.

In some embodiments, the disorder or disease is a bone or cartilagedisease.

In some embodiments, the disorder or disease is Alzheimer's disease.

In some embodiments, the disorder or disease is osteoarthritis.

In some embodiments, the disorder or disease is lung disease

In some embodiments, the disorder or disease is a genetic disease causedby mutations in Wnt signaling components, wherein the genetic disease isselected from: polyposis coli, osteoporosis-pseudoglioma syndrome,familial exudative vitreoretinopathy, retinal angiogenesis, earlycoronary disease, tetra-amelia syndrome, Müllerian-duct regression andvirilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmannsyndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletaldysplasia, focal dermal hypoplasia, autosomal recessive anonychia,neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile Xsyndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome,Beckwith-Wiedemann Syndrome, Norrie disease, and Rett syndrome.

In some embodiments, the patient is a human.

In some embodiments, the cancer is chosen from: hepatocellularcarcinoma, colon cancer, breast cancer, pancreatic cancer, chronicmyeloid leukemia (CML), chronic myelomonocytic leukemia, chroniclymphocytic leukemia (CLL), acute myeloid leukemia, acute lymphocyticleukemia, Hodgkin lymphoma, lymphoma, sarcoma, and ovarian cancer.

In some embodiments, the cancer is chosen from: lung cancer—non-smallcell, lung cancer—small cell, multiple myeloma, nasopharyngeal cancer,neuroblastoma, osteosarcoma, penile cancer, pituitary tumors, prostatecancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skincancer—basal and squamous cell, skin cancer—melanoma, small intestinecancer, stomach cancers, testicular cancer, thymus cancer, thyroidcancer, uterine sarcoma, vaginal cancer, vulvar cancer, laryngeal orhypopharyngeal cancer, kidney cancer, Kaposi sarcoma, gestationaltrophoblastic disease, gastrointestinal stromal tumor, gastrointestinalcarcinoid tumor, gallbladder cancer, eye cancer (melanoma and lymphoma),Ewing tumor, esophagus cancer, endometrial cancer, colorectal cancer,cervical cancer, brain or spinal cord tumor, bone metastasis, bonecancer, bladder cancer, bile duct cancer, anal cancer, and adrenalcortical cancer.

In some embodiments, the cancer is hepatocellular carcinoma.

In some embodiments, the cancer is colon cancer.

In some embodiments, the cancer is breast cancer.

In some embodiments, the cancer is pancreatic cancer.

In some embodiments, the cancer is chronic myeloid leukemia (CML).

In some embodiments, the cancer is chronic myelomonocytic leukemia.

In some embodiments, the cancer is chronic lymphocytic leukemia (CLL).

In some embodiments, the cancer is acute myeloid leukemia.

In some embodiments, the cancer is acute lymphocytic leukemia.

In some embodiments, the cancer is Hodgkin lymphoma.

In some embodiments, the cancer is lymphoma.

In some embodiments, the cancer is sarcoma.

In some embodiments, the cancer is ovarian cancer.

In some embodiments, the cancer is lung cancer—non-small cell.

In some embodiments, the cancer is lung cancer—small cell.

In some embodiments, the cancer is multiple myeloma.

In some embodiments, the cancer is nasopharyngeal cancer.

In some embodiments, the cancer is neuroblastoma.

In some embodiments, the cancer is osteosarcoma.

In some embodiments, the cancer is penile cancer.

In some embodiments, the cancer is pituitary tumors.

In some embodiments, the cancer is prostate cancer.

In some embodiments, the cancer is retinoblastoma.

In some embodiments, the cancer is rhabdomyosarcoma.

In some embodiments, the cancer is salivary gland cancer.

In some embodiments, the cancer is skin cancer—basal and squamous cell.

In some embodiments, the cancer is skin cancer—melanoma.

In some embodiments, the cancer is small intestine cancer.

In some embodiments, the cancer is stomach cancers.

In some embodiments, the cancer is testicular cancer.

In some embodiments, the cancer is thymus cancer.

In some embodiments, the cancer is thyroid cancer.

In some embodiments, the cancer is uterine sarcoma.

In some embodiments, the cancer is vaginal cancer.

In some embodiments, the cancer is vulvar cancer.

In some embodiments, the cancer is Wilms tumor.

In some embodiments, the cancer is laryngeal or hypopharyngeal cancer.

In some embodiments, the cancer is kidney cancer.

In some embodiments, the cancer is Kaposi sarcoma.

In some embodiments, the cancer is gestational trophoblastic disease.

In some embodiments, the cancer is gastrointestinal stromal tumor.

In some embodiments, the cancer is gastrointestinal carcinoid tumor.

In some embodiments, the cancer is gallbladder cancer.

In some embodiments, the cancer is eye cancer (melanoma and lymphoma).

In some embodiments, the cancer is Ewing tumor.

In some embodiments, the cancer is esophagus cancer.

In some embodiments, the cancer is endometrial cancer.

In some embodiments, the cancer is colorectal cancer.

In some embodiments, the cancer is cervical cancer.

In some embodiments, the cancer is brain or spinal cord tumor.

In some embodiments, the cancer is bone metastasis.

In some embodiments, the cancer is bone cancer.

In some embodiments, the cancer is bladder cancer.

In some embodiments, the cancer is bile duct cancer.

In some embodiments, the cancer is anal cancer.

In some embodiments, the cancer is adrenal cortical cancer.

In some embodiments, the disorder or disease is a neurologicalcondition, disorder or disease, wherein the neurologicalcondition/disorder/disease is selected from: Alzheimer's disease,frontotemporal dementias, dementia with lewy bodies, prion diseases,Parkinson's disease, Huntington's disease, progressive supranuclearpalsy, corticobasal degeneration, multiple system atrophy, amyotrophiclateral sclerosis (ALS), inclusion body myositis, autism, degenerativemyopathies, diabetic neuropathy, other metabolic neuropathies, endocrineneuropathies, orthostatic hypotension, multiple sclerosis, andCharcot-Marie-Tooth disease.

In some embodiments, the compound of Formulas (I) and/or (Ia) inhibitsone or more proteins in the Wnt pathway.

In some embodiments, the compound of Formulas (I) and/or (Ia) inhibitssignaling induced by one or more Wnt proteins.

In some embodiments, the Wnt proteins are chosen from: WNT1, WNT2,WNT2B, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A,WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, and WNT16.

In some embodiments, the compounds of Formulas (I) and/or (Ia) inhibit akinase activity.

In some embodiments, a method for treating a disease or disordermediated by the Wnt pathway in a patient is provoided, the methodcomprises administering to the patient a therapeutically effectiveamount of a compound (or compounds) of Formulas (I) and/or (Ia), or apharmaceutically acceptable salt thereof.

In some embodiments, the compounds of Formulas (I) and/or (Ia) inhibitone or more Wnt proteins.

In some embodiments, a method for treating a disease or disordermediated by kinase activity in a patient is provided, the methodcomprises administering to the patient a therapeutically effectiveamount of a compound (or compounds) of Formulas (I) and/or (Ia), or apharmaceutically acceptable salt thereof.

In some embodiments, the disease or disorder comprises tumor growth,cell proliferation, or angiogenesis.

In some embodiments, the method inhibits the activity of a proteinkinase receptor, the method comprises contacting the receptor with aneffective amount of a compound (or compounds) of Formulas (I) and/or(Ia), or a pharmaceutically acceptable salt thereof.

In some embodiments, a method for treating a disease or disorderassociated with aberrant cellular proliferation in a patient isprovided, the method comprises administering to the patient atherapeutically effective amount of a compound (or compounds) ofFormulas (I) and/or (Ia), or a pharmaceutically acceptable salt thereof.

In some embodiments, the method prevents or reduces angiogenesis in apatient; the method comprises administering to the patient atherapeutically effective amount of a compound (or compounds) ofFormulas (I) and/or (Ia), or a pharmaceutically acceptable salt thereof.

In some embodiments, the method prevents or reduces abnormal cellularproliferation in a patient; the method comprises administering to thepatient a therapeutically effective amount of a compound (or compounds)of Formulas (I) and/or (Ia), or a pharmaceutically acceptable saltthereof.

In some embodiments, a method for treating a disease or disorderassociated with aberrant cellular proliferation in a patient isprovided, the method comprises administering to the patient apharmaceutical composition comprising one or more of the compounds ofFormulas (I) and/or (Ia) in combination with a pharmaceuticallyacceptable carrier and one or more other agents.

Moreover, the compounds and compositions, for example, as inhibitors ofthe cyclin-dependent kinases (CDKs), can modulate the level of cellularRNA and DNA synthesis and therefore are expected to be useful in thetreatment of viral infections such as HIV, human papilloma virus, herpesvirus, Epstein-Barr virus, adenovirus, Sindbis virus, pox virus, and thelike.

Compounds and compositions described herein can inhibit the kinaseactivity of, for example, CDK/cyclin complexes, such as those active inthe G₀ or G₁ stage of the cell cycle, e.g., CDK2, CDK4, and/or CDK6complexes.

Evaluation of Biological Activity

The biological activity of the compounds described herein can be testedusing any suitable assay known to those of skill in the art, see e.g.,WO 2001/053268 or WO 2005/009997. For example, the activity of acompound may be tested using one or more of the test methods outlinedbelow.

In one example, tumor cells may be screened for Wnt independent growth.In such a method, tumor cells of interest are contacted with a compound(i.e. inhibitor) of interest, and the proliferation of the cells, e.g.by uptake of tritiated thymidine, is monitored. In some embodiments,tumor cells may be isolated from a candidate patient who has beenscreened for the presence of a cancer that is associated with a mutationin the Wnt signaling pathway. Candidate cancers include, withoutlimitation, those listed above.

In another example, in vitro assays for Wnt biological activity may beused, e.g. stabilization of β-catenin and promoting growth of stemcells. Assays for biological activity of Wnt include stabilization ofβ-catenin, which can be measured, for example, by serial dilutions of acandidate inhibitor composition. An exemplary assay for Wnt biologicalactivity contacts a Wnt composition in the presence of a candidateinhibitor with cells, e.g. mouse L cells. The cells are cultured for aperiod of time sufficient to stabilize β-catenin, usually at least about1 hour, and lysed. The cell lysate is resolved by SDS PAGE, thentransferred to nitrocellulose and probed with antibodies specific forβ-catenin.

In a further example, the activity of a candidate compound can bemeasured in a Xenopus secondary axis bioassay [Leyns, L. et al. Cell(1997), 88(6), 747-756].

To further illustrate this disclosure, the following examples areincluded. The examples should not, of course, be construed asspecifically limiting the disclosure. Variations of these exampleswithin the scope of the claims are within the purview of one skilled inthe art and are considered to fall within the scope of the invention asdescribed, and claimed herein. The reader will recognize that theskilled artisan, armed with the present disclosure, and skill in the artis able to prepare and use the invention without exhaustive examples.

EXAMPLES Compound Preparation

The starting materials used in preparing the compounds of the disclosureare known, made by known methods, or are commercially available. It willbe apparent to the skilled artisan that methods for preparing precursorsand functionality related to the compounds claimed herein are generallydescribed in the literature. The skilled artisan given the literatureand this disclosure is well equipped to prepare any of the compounds.

It is recognized that the skilled artisan in the art of organicchemistry can readily carry out manipulations without further direction,that is, it is well within the scope and practice of the skilled artisanto carry out these manipulations. These include reduction of carbonylcompounds to their corresponding alcohols, oxidations, acylations,aromatic substitutions, both electrophilic and nucleophilic,etherifications, esterification and saponification and the like. Thesemanipulations are discussed in standard texts such as March's AdvancedOrganic Chemistry: Reactions, Mechanisms, and Structure 7^(th) Ed., JohnWiley & Sons (2013), Carey and Sundberg, Advanced Organic Chemistry5^(th) Ed., Springer (2007), Comprehensive Organic Transformations: AGuide to Functional Group Transformations, 2^(nd) Ed., John Wiley & Sons(1999) and the like.

The skilled artisan will readily appreciate that certain reactions arebest carried out when other functionality is masked or protected in themolecule, thus avoiding any undesirable side reactions and/or increasingthe yield of the reaction. Often the skilled artisan utilizes protectinggroups to accomplish such increased yields or to avoid the undesiredreactions. These reactions are found in the literature and are also wellwithin the scope of the skilled artisan. Examples of many of thesemanipulations can be found for example in T. Greene and P. WutsProtective Groups in Organic Synthesis, 4th Ed., John Wiley & Sons(2007).

Trademarks used herein are examples only and reflect illustrativematerials used at the time of filing the present disclosure. The skilledartisan will recognize that variations in lot, manufacturing processes,and the like, are expected. Hence the examples, and the trademarks usedin them are non-limiting, and they are not intended to be limiting, butare merely an illustration of how a skilled artisan may choose toperform one or more of the embodiments of the disclosure.

(¹H) nuclear magnetic resonance spectra (NMR) were measured in theindicated solvents on a Bruker NMR spectrometer (Avance™ DRX300, 300 MHzfor ¹H or Avance™ DRX500, 500 MHz for ¹H) or Varian NMR spectrometer(Mercury 400BB, 400 MHz for ¹H). Peak positions are expressed in partsper million (ppm) downfield from tetramethylsilane. The peakmultiplicities are denoted as follows, s, singlet; d, doublet; t,triplet; q, quartet; ABq, AB quartet; quin, quintet; sex, sextet; sep,septet; non, nonet; dd, doublet of doublets; d/ABq, doublet of ABquartet; dt, doublet of triplets; td, triplet of doublets; dq, doubletof quartets; m, multiplet.

The following abbreviations have the indicated meanings:

brine=saturated aqueous sodium chloride

CDCl₃=deuterated chloroform

CsCO₃=cesium carbonate

DCE=dichloroethane

DCM=dichloromethane

DHP=3,4-dihydro-2H-pyran

DMF=N,N-dimethylformamide

DMSO-d₆=deuterated dimethylsulfoxide

ESIMS=electron spray mass spectrometry

EtOAc=ethyl acetate

Et₃SiH=triethylsilane

HCl=hydrochloric acid

HOAc=acetic acid

KOAc=potassium acetate

KOH=potassium hydroxide

K₃PO₄=potassium phosphate

LAH=lithium aluminum hydride

MeOH=methanol

MgSO₄=magnesium sulfate

NaBH(OAc)₃=sodium triacetoxy borohydride

Na₂CO₃=sodium carbonate

NaHCO₃=sodium bicarbonate

NaHSO₃=sodium bisulfite

NaOAc=sodium acetate

NMR=nuclear magnetic resonance

Pd/C=palladium on carbon

Pd₂(dba)₃=tris(dibenzylideneacetone)dipalladium(0)

PdClz₂(dppf)₂=1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride

Pd(PPh₃)₂Cl₂=dichloro-bis(triphenylphosphine)palladium (II)

Pd(PPh₃)₄=tetrakis(triphenylphosphine)palladium(0)

PE=petroleum ether

PPTS=pyridinium p-toluenesulfonate

rt=room temperature

SEM=2-(trimethylsilyl)ethoxymethyl

TFA=trifluoroacetic acid

THF=tetrahydrofuran

TLC=thin layer chromatography

The following example schemes are provided for the guidance of thereader, and collectively represent an example method for making thecompounds provided herein. Furthermore, other methods for preparingcompounds of the disclosure will be readily apparent to the person ofordinary skill in the art in light of the following reaction schemes andexamples. The skilled artisan is thoroughly equipped to prepare thesecompounds by those methods given the literature and this disclosure. Thecompound numberings used in the synthetic schemes depicted below aremeant for those specific schemes only, and should not be construed as orconfused with same numberings in other sections of the application.Unless otherwise indicated, all variables are as defined above.

General Procedures

Compounds of Formulas (I) and/or (Ia) of the present disclosure can beprepared as depicted in Scheme 1.

Scheme 1 describes a method for preparation of indazole derivatives (IX)by first formylating 5-bromo-1H-indole (I) to produce5-bromo-1H-indazole-3-carbaldehyde (II) followed by protection withSEM-Cl to give5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbaldehyde(III). Bromide (III) is then reacted with bis(pinacolato)diboron to formthe borate ester (IV). Suzuki coupling with various bromides (V) yieldsindazole derivatives (VI). Aldehyde (VI) is reacted with various1,2-diamines (VII) to produce (VIII). Final deprotection of the pyrazolenitrogen yields the desired indazole derivatives (IX).

Illustrative Compound Examples

Preparation of intermediate (IV) is depicted below in Scheme 2.

Step 1

A solution of NaNO₂ (110.4 g, 1.6 mol, 8 eq) in water (200 mL) was addeddropwise to a solution of 5-bromoindole (I) (39.2 g, 0.2 mol, 1 eq) inacetone (1000 mL) stirred at -10-−0° C., while adding NaNO₂ the solutiontemperature was maintained below 20° C. An aqueous 2N HCl solution (480mL) was added slowly to the solution with vigorously stirring whilekeeping the internal temperature between 0 and 20° C. The solution wasfurther stirred at 20° C. for 3 h after the addition. The solution wasconcentrated under reduced pressure to remove acetone while keeping thetemperature below 35° C. The solid was collected by filtration andtransferred to a flask. Cold (−10° C.) DCM (200 mL) was added andstirred for 30 min at −5° C., the solids were filtered and dried undervacuum at 40° C. to get 5-bromo-1H-indazole-3-carbaldehyde (II) (34.0 g,151 mmol, 76% yield) as a brown solid. ESIMS found for C₈H₅BrN₂O m/z 225(M+H).

Step 2

To a suspension of NaH (6.6 g, 166 mmol, 1.10 eq) in DMF (500 mL) wasadded a solution of 5-bromo-1H-indazole-3-carbaldehyde (II) (34.0 g, 151mmol, 1.00 eq) in DMF (50 mL) dropwise at 0° C. over a period of 30 min.The mixture was stirred at room temperature for 2 h, then SEM-Cl (26.4g, 159 mmol, 1.08 eq) was added dropwise and the mixture was stirred atroom temperature for another 3 h. Then the mixture was poured into anice-water mixture (1000 mL) and extracted with EtOAc (300 mL×3), theorganic phases were combined, dried over Na₂SO₄, filtered andconcentrated in vacuo, the resultant residue was purified by flashchromatography on silica gel (PE:EtOAc=20:1-10:1) to afford5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbaldehyde(III) as a mixture of regioisomers (53.0 g, 151 mmol, 100% yield) as ayellow oil. ESIMS found for C₁₄H₁₉BrN₂O₂Si m/z 355 (M+H).

Step 3

To a solution of the mixed 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbaldehyde (III) (53.0 g, 151 mmol, 1.0 eq),bis(pinacolato)diboron (38.0 g, 150 mmol, 1.0 eq) and KOAc (44.0 g, 450mmol, 3.00 eq) in DMF (1000 mL) was added Pd(dppf)Cl₂ (7.7 g, 10.5 mmol,0.07 eq). The mixture was stirred at 90° C. under nitrogen for 10 h. Themixture was filtered; the filtrate was poured onto water (1000 mL) andextracted with EtOAc (500 mL×3). The combined organic phases were dried,filtered and concentrated in vacuo. The resultant residue was purifiedby flash chromatography on silica gel (PE:EtOAc=10:1-1:1) to give the5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbaldehyde(IV) as a mixture of regioisomers (42.9 g, 106 mmol, 71% yield) as ayellow oil. ESIMS found for C₂₀H₃₁BN₂O₄Si m/z 403 (M+H).

Preparation of intermediate N-(5-bromopyridin-3-yl)isobutyramide (VII)is depicted below in Scheme 3.

Step 1

3-Amino-5-bromo pyridine (V) (1 eq) was dissolved in DCM and cooled to0° C. before adding pyridine (2.2 eq) and isobutyryl chloride (VI) (1.1eq). The reaction mixture was stirred at r.t. for 15 h until TLC showedthe reaction was complete. The reaction mixture was diluted with DCM andwashed with water. The organic extract was dried, concentrated andpurified by column chromatography using silica gel (100-200 mesh) toafford N-(5-bromopyridin-3-yl)isobutyramide (VII) as an off-white solid,(71% yield). ¹H NMR (CDCl₃) δ ppm 8.55-8.35 (m, 3H), 7.32 (s, 1H),2.59-2.48 (m, 1H), 1.28-1.27 (d, 6H); ESIMS found C₉H₁₁BrN₂O m/z 243.05(M+H).

The following compounds were prepared in accordance with the proceduredescribed in the above Scheme 3.

N-(5-Bromopyridin-3-yl)propionamide (VIII): Off white solid (92% yield).¹H NMR (DMSO-d₆) δ ppm 1.09 (t, J=7.54 Hz, 3H), 2.36 (q, J=7.54 Hz, 2H),8.36 (m, 2H), 8.65 (d, J=2.07 Hz, 1H), 10.26 (s, 1H); ESIMS foundCsH₉BrN₂O m/z 231 (M+H).

N-(5-Bromopyridin-3-yl)butyramide (IX): Yellow solid (2.1 g, 8.64 mmol,88.8% yield). ESIMS found C₉H₁₁BrN₂O m/z 243 (M+H).

N-(5-Bromopyridin-3-yl)pentanamide (X): Yellow solid (2.0 g, 7.78 mmol,85.3% yield). ESIMS found C₁₀H₁₃BrN₂O m/z 257 (M+H).

N-(5-Bromopyridin-3-yl)-3-methylbutanamide (XI): Off white solid, (67%yield), ¹H NMR (CDCl₃, 400 MHz) δ ppm 8.55-8.42 (m, 3H), 7.62 (s, 1H),2.31-2.18 (m, 3H), 1.02-1.01 (d, J=6 Hz, 6H); ESIMS found C₁₀H₁₃BrN₂Om/z 258.80 (M+H).

N-(5-Bromopyridin-3-yl)-3,3-dimethylbutanamide (XII): Yellow solid (1.7g, 6.27 mmol, 78.6% yield). ESIMS found C₁₁H₁₅BrN₂O m/z 271 (M+H).

N-(5-Bromopyridin-3-yl)pivalamide (XIII): Off-white solid (1.082 g, 4.22mmol, 73.1% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 1.23 (s, 9H), 8.37(d, J=2 Hz, 1H), 8.39 (t, J=2 Hz, 1H), 8.80 (d, J=2 Hz, 1H), 9.58 (brs,1H); ESIMS found C₁₀H₁₃BrN₂O m/z 257.0 (M+H).

N-(5-Bromopyridin-3-yl)-2-phenylacetamide (XIV): White solid (2.5 g,8.59 mmol, 77.9% yield). ESIMS found C₁₃H₁₁BrN₂O m/z 291 (M+H).

N-(5-Bromopyridin-3-yl)benzamide (XV): White solid (2.7 g, 9.74 mmol,60% yield). ESIMS found C₁₂H₉BrN₂O m/z 277 (M+H).

N-(5-Bromopynridin-3-yl)cyclopropanecarboxamide (XVI): Off-white solid,(83% yield), ¹H NMR (CDCl₃, 400 MHz) δ ppm 8.46-8.39 (m, 3H), 7.54 (bs,1H), 1.56-1.50 (m, 1H), 1.13-1.07 (m, 2H), 0.96-0.90 (m, 2H); ESIMSfound for C₉H₉BrN₂O m/z 240.9 (M+H).

N-(5-Bromopyridin-3-yl)cyclobutanecarboxamide (XVII): Yellow solid (2.1g, 6.27 mmol, 86.6% yield). ESIMS found C₁₀H₁₁BrN₂O m/z 255 (M+H).

N-(5-Bromopyridin-3-yl)cyclopentanecarboxamide (XVIII): Yellow solid(1.9 g, 7.06 mmol, 80.2% yield). ESIMS found C₁₁H₁₃BrN₂O m/z 269 (M+H).

N-(5-bromopyridin-3-yl)cyclohexanecarboxamide (XIX): Yellow solid (2.0g, 7.06 mmol, 84.3% yield). ESIMS found C₁₂H₁₅BrN₂O m/z 283 (M+H).

Preparation of intermediate 5-bromo-N,N-dimethylpyridin-3-amine (XXI) isdepicted below in Scheme 4.

Step 1

To a solution of 3,5-dibromopyridine (XX) (2.37 g, 10.0 mmol) in dry DMF(20.0 mL) was added K₂CO₃ (4.5 g, 33 mmol) and dimethylaminohydrochloride (1.79 g, 22 mmol). The mixture was heated overnight at200° C. in a sealed tube. The solution was cooled to room temperatureand excess DMF was removed under vacuum. The residue was partitionedbetween EtOAc and water. The organic phase was separated. The aqueousphase was washed with EtOAc and the combined organic phases were driedover MgSO₄, and concentrated to afford5-bromo-N,N-dimethylpyridin-3-amine (XXI) as an off-white solid (1.78 g,8.85 mmol, 88% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 2.94 (s, 6H),7.25 (t, J=2 Hz, 1H), 7.91 (d, J=2 Hz, 1H), 8.07 (d, J=2 Hz, 1H); ESIMSfound C₇H₉BrN₂ m/z 201.1 (M+H).

Preparation of intermediate 5-bromo-N-isopropylpyridin-3-amine (XXIII)is depicted below in Scheme 5.

Steps 1

To a solution of 5-bromopyridin-3-amine (XXII) (535 mg, 3.09 mmol) inMeOH (62 mL) was added acetone (296 μL, 4.02 mL). The pH was adjusted to4 using HOAc and stirred for 30 min. NaCNBH₃ (272 mg, 4.33 mmol) wasadded and stirred at room temperature overnight. The MeOH was removedunder vacuum and the residue was partitioned between EtOAc and saturatedaqueous NaHCO₃. The organic layer was dried over MgSO₄ and evaporatedunder vacuum. The crude product was purified on a silica gel column(100% hexane→90:10 hexane:EtOAc) to produce5-bromo-N-isopropylpyridin-3-amine (XXIII) as an oil which slowlysolidified into an off-white solid (309 mg, 1.44 mmol, 47% yield). ¹HNMR (DMSO-d₆, 500 MHz) δ ppm 1.12 (d, J=6.3 Hz, 6H), 3.55-3.59 (m, 1H),6.03 (d, J=7.9 Hz, 1H), 7.05-7.06 (m, 1H), 7.75 (d, J=2 Hz, 1H), 7.90(d, J=2 Hz, 1H); ESIMS found C₈H₁₁BrN₂ m/z 215 (M+H).

Preparation of intermediate 1-(5-bromopyridin-3-yl)-N,N-dimethylmethanamine (XXV) is depicted below in Scheme 6.

Step 1

To a solution of 5-bromonicotinaldehyde (XXIV) (5.0 g, 26.9 mmol) in DCE(108 mL) was added dimethylamine-HC (4.39 g, 53.8 mmol) and TEA (7.5 g,53.8 mmol). The reaction was stirred at room temperature for 1 h.NaBH(OAc)₃ was added and the reaction was stirred overnight at roomtemperature. The reaction was diluted with DCM and sat. aq. NaHCO₃. Theorganic layer was separated, washed with water, brine, dried andconcentrated under vacuum to produce1-(5-bromopyridin-3-yl)-N,N-dimethylmethanamine (XXV) as a brown liquid(5.36 g, 24.9 mmol, 92.6% yield). ¹H NMR (CDCl₃) δ ppm 2.15 (s, 6H),3.43 (s, 2H), 7.94 (s, 1H), 8.47 (d, J=1.1 Hz, 1H), 8.59 (d, J=2.2 Hz,1H); ESIMS found C₈H₁₁BrN₂ m/z 215 (M^(Br79)+H) and 217 (M^(Br81)+H).

The following intermediates were prepared in accordance with theprocedure described in the above Scheme 6.

3-Bromo-5-(pyrrolidin-1-ylmethyl)pyridine (XXVI): Golden liquid (1.35 g,97% yield). ¹H NMR (DMSO-d₆) 1.68-1.71 (m, 4H), 2.42-2.44 (m, 4H), 3.60(s, 2H), 7.96 (s, 1H), 8.48 (d, J=2 Hz, 1H), 8.58 (d, J=3 Hz, 1H); ESIMSfound for C₁₀H₁₃BrN₂ m/z 242 (M+H).

3-Bromo-5-(piperidin-1-ylmethyl)pyridine (XXVII): Brown liquid (13.1 g,94% yield). ¹H NMR (DMSO-d₆) 1.36-1.39 (m, 2H), 1.46-1.51 (m, 4H),2.31-2.32 (m, 4H), 3.46 (s, 2H), 7.94 (s, 1H), 8.47 (d, J=2 Hz, 1H),8.58 (d, J=3 Hz, 1H); ESIMS found for C₁₁H₁₅BrN₂ m/z 257 (M+H).

N-((5-Bromopyridin-3-yl)methyl)ethanamine (XXVIII): Golden liquid (1.29g, 6.00 mmol, 60% yield ESIMS found for C₈H₁₁Br₂N₂ m/z 215 (M+H).

N-Benzyl-1-(5-bromopyridin-3-yl)methanamine (XXIX): Golden liquid (77mg, 0.28 mmol, 25% yield). ESIMS found for C₁₃H₁₃BrN₂ m/z 277 (M+H).

Preparation of intermediate tert-butyl (5-bromopyridin-3-yl)methyl(cyclopentylmethyl)carbamate (XXXIV) is depicted below in Scheme 7.

Step 1

To a solution of 5-bromonicotinaldehyde (XXIV) (2.0 g, 10.8 mmol, 1 eq)in MeOH (20 mL) was added NaBH₄ (2.4 g, 64.9 mmol, 6 eq) and thereaction mixture was stirred at room temperature for 3 h. The mixturewas concentrated in vacuo and the residue was diluted in water (15 mL),the aqueous phase was extracted with DCM (10 mL×3). The combined organiclayers were dried over MgSO₄, filtered and concentrated in vacuo toafford (5-bromopyridin-3-yl)methanol (XXX) (1.8 g, 9.57 mmol, 90.0%yield) as a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ ppm 4.73 (s, 2H),7.90 (s, 1H), 8.47 (s, 1H), 8.57 (s, 1H). ESIMS found for C₆H₆BrNO m/z188 (M+H).

Step 2

To a stirred solution of (5-bromopyridin-3-yl)methanol (XXX) (1.60 g,8.5 mmol, 1 eq), phthalimide (1.24 g, 8.5 mmol, 1 eq) and PPh₃ (3.33 g,12.75 mmol, 1.5 eq) in anhydrous THF (15 mL) was added DEAD (2.21 g,12.75 mmol, 1.5 eq) dropwise at 0° C. under N₂. Then the reactionmixture was stirred at room temperature for 6 h. The mixture was washedwith saturated NaHCO₃ solution (15 mL), water (15 mL) and brine (15 mL)subsequently. The organic layers were dried over MgSO₄, concentratedunder reduced pressure, the resultant residue was purified by flashchromatography on silica gel (PE:EtOAc=4:1) to give2-((5-bromopyridin-3-yl)methyl)isoindoline-1,3-dione (XXXI) (2.5 g, 7.88mmol, 82.3% yield) as a white solid. ESIMS found for C₁₄H₉BrN₂O₂ m/z 317(M+H).

Step 3

A solution of 2-((5-bromopyridin-3-yl)methyl)isoindoline-1,3-dione(XXXI) (1.9 g, 6.0 mmol, 1 eq) and hydrazine hydrate (2.0 g, 40 mmol, 6eq) in EtOH (20 mL) was heated at 70° C. for 3 h. The mixture wasfiltered through a Celite pad and the filtrate was concentrated invacuo, the crude product was dissolved in 1N HCl solution (15 mL) andconcentrated to dryness, then it was washed with acetone (10 mL×3), theprecipitate was collected by filtration, dried in vacuo to give(5-bromopyridin-3-yl)methanamine (XXXII) (1.3 g, 6.95 mmol, 97.7% yield)as a white solid. ¹H NMR (D₂O, 400 MHz) δ ppm 4.34 (s, 2H), 8.56 (s,1H), 8.75 (d, J=1.2 Hz, 1H), 8.91 (d, J=1.6 Hz, 1H). ESIMS found forC₆H₇BrN₂ m/z 187 (M+H).

Step 4

A solution of (5-bromopyridin-3-yl)methanamine (XXXII) (1.30 g, 5.8mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) andTEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at roomtemperature for 2 h. Then NaBH₃CN (1.98 g, 34.6 mmol, 6.0 eq) was addedand the mixture was stirred at the same temperature for another 3 h. Thesolvent was removed under reduced pressure and the residue was dilutedin water (20 mL) and extracted with DCM (10 mL×3), combined organiclayers were dried over MgSO₄ and concentrated in vacuo to give1-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (XXXIII) (1.23g, 4.57 mmol, 79.3% yield) as a brown oil. ESIMS found for C₁₂H₁₇BrN₂m/z 269 (M+H).

Step 5

To a solution of 1-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (XXXIII) (1.00 g, 3.7 mmol, 1 eq) and TEA (0.93 g, 9.2 mmol,2.5 eq) in DCM (20 mL) was added portionwise (Boc)₂O (0.85 g, 4.0 mmol,1.1 eq) at 0° C., the reaction mixture was stirred at room temperaturefor 1 h. The mixture was washed with water (10 mL), brine (10 mL), theorganic layer was separated, dried over MgSO₄ and concentrated in vacuoto give tert-butyl (5-bromopyridin-3-yl)methyl(cyclopentylmethyl)carbamate (XXXIV) (1.25 g, 3.38 mmol, 91.9% yield) asa white solid. ESIMS found for C₁₇H₂₅BrN₂O₂ m/z 369 (M+H).

Preparation of intermediate3-(4-methyl-imidazol-1-yl)-benzene-1,2-diamine (XXXVII) is depictedbelow in Scheme 8.

Step 1

A solution of 3-chloro-2-nitro-aniline (XXXV) (1.0 g, 5.8 mmol),potassium carbonate (2.4 g, 17.4 mmol), and 4-methylimidazole in dry DMFwas heated overnight at 120° C. under nitrogen. The reaction was cooledand the solvent was evaporated in vacuo. The residue was suspended in asaturated NaHCO₃ solution and extracted with CH₂Cl₂. The combinedorganic phases were dried over MgSO₄ and concentrated in vacuo. Thecrude product was purified by flash chromatography to provide3-(4-methyl-imidazol-1-yl)-2-nitro-phenylamine (XXXVI). ¹H NMR (CDCl₃,400 MHz) δ ppm 2.19 (s, 3H), 6.53 (m, 1H), 6.79 (m, 1H), 6.93 (m, 1H),7.32 (m, 1H), 7.60 (m, 1H).

Step 2

To a solution of 3-(4-methyl-imidazol-1-yl)-2-nitro-phenylamine (XXXVI)in MeOH was added with 5% Pd/C. The combination was stirred under ahydrogen filled balloon at 40° C. for 6 h. The solution was thenfiltered through a pad of Celite. The filtrate was concentrated in vacuoto get 3-(4-methyl-imidazol-1-yl)-benzene-1,2-diamine (XXXVII). ¹H NMR(CDCl₃, 400 MHz) δ ppm 2.17 (s, 3H), 6.54 (m, 1H), 6.80 (m, 1H), 6.97(m, 1H), 7.28 (m, 1H), 7.56 (m, 1H).

Preparation of intermediate 2′-fluorobiphenyl-2,3-diamine (XLI) isdepicted below in Scheme 9.

Step 1

A solution of 3-bromo-2-nitroaniline (XXXVIII) (2.00 g, 9.30 mmol, 1eq), 2-fluorophenylboronic acid (XXXIX) (1.42 g, 10.14 mmol, 1.1 eq),Pd(PPh₃)₄ (0.35 g, 0.03 mmol, 0.03 eq), Na₂CO₃ (1.95 g, 18.40 mmol, 2eq) in a mixed solvent of toluene (15 mL), H₂O (9 mL) and EtOH (3 ml)was stirred at 75° C. for 15 h under nitrogen atmosphere. Then thereaction mixture was washed with brine (20 mL) and dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo, the resultant residue waspurified by chromatography on silica gel (PE:EtOAc=3:1) to afford2′-fluoro-2-nitrobiphenyl-3-amine (XL) (1.0 g, 4.30 mmol, 46.6% yield)as a yellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm 6.54 (d, J=6.4 Hz,1H), 6.64 (s, 2H), 7.04 (dd, J=8.8 Hz, J=1.2 Hz, 1H), 7.18-7.31 (m, 2H),7.33-7.47 (m, 3H); ESIMS found for C₁₂H₉FN₂O₂ m/z 233 (M+H).

Step 2

To a solution of 2′-fluoro-2-nitrobiphenyl-3-amine (XL) (1.0 g, 3.45mmol, 1 eq) in MeOH (50 mL) was added Pd/C (0.5 g) under nitrogenatmosphere, the mixture was stirred under 50 psi of H₂ for 6 h at roomtemperature. Then the mixture was filtered and concentrated in vacuo toafford 2′-fluorobiphenyl-2,3-diamine (XLI) (0.8 g, 3.96 mmol, 92% yield)as a black solid. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm 3.99 (s, 2H), 4.62 (s,2H), 6.32 (d, J=7.6 Hz, 1H), 6.49 (t, J=7.6 Hz, 1H), 6.60 (d, J=7.6 Hz,1H), 7.21-7.35 (m, 3H), 7.35-7.45 (m, 1H); ESIMS found for C₁₂H₁₁FN₂ m/z203 (M+H).

The following intermediates were prepared in accordance with theprocedure described in the above Scheme 9.

3′-Fluorobiphenyl-2,3-diamine (XLII): White solid (2.0 g, 9.89 mmol, 81%yield). ¹H NMR (DMSO-d₆, 400 MHz) δ ppm 4.16 (s, 2H), 4.64 (s, 2H), 6.38(dd, J=7.6 Hz, J=1.6 Hz, 1H), 6.51 (t, J=7.6 Hz, 1H), 6.60 (d, J=6 Hz,1H), 7.11-7.26 (m, 3H), 7.48 (q, J=6.4 Hz, 1H); ESIMS found forC₁₂H₁₁FN₂ m/z 203 (M+H).

4′-Fluorobiphenyl-2,3-diamine (XLIII): White solid (2.4 g, 11.87 mmol,98% yield). ¹H NMR (DMSO-d₆, 400 MHz) δ ppm 4.07 (s, 2H), 4.60 (s, 2H),6.34 (dd, J=7.6 Hz, J=1.6 Hz, 1H), 6.50 (t, J=7.6 Hz, 1H), 6.58 (dd,J=7.6 Hz, J=1.6 Hz, 1H), 7.26 (t, J=7.6 Hz, 2H), 7.40 (q, J=5.6 Hz, 2H);ESIMS found for C₁₂H₁₁FN₂ m/z 203 (M+H).

3-(Pyridin-3-yl)benzene-1,2-diamine (XLIV): White solid (1.36 g, 7.34mmol, 92.5% yield). ¹H NMR (CDCl₃, 400 MHz) δ ppm 1.57 (brs, 2H), 3.42(brs, 2H), 6.66 (dd, J=6 Hz, J=3.2 Hz, 1H), 6.68-6.72 (m, 2H), 7.31 (dd,J=8 Hz, J=4.8 Hz, 1H), 7.71 (td, J=8 Hz, J=2 Hz, 1H), 8.54 (dd, J=4.8Hz, J=1.6 Hz, 1H), 8.64 (d, J=1.6 Hz, 1H); ESIMS found for C₁₁H₁₁N₃ m/z186 (M+H).

3-(Thiophen-3-yl)benzene-1,2-diamine (XLV): White solid (1.2 g, 6.31mmol, mmol, 94% yield). ¹H NMR (DMSO-d₆, 400 MHz) δ ppm 4.19 (s, 2H),4.59 (s, 2H), 6.47 (dd, J=4.8 Hz, J=1 Hz, 2H), 6.55 (q, J=4.8 Hz, 1H),7.24 (dd, J=4.8 Hz, J=1 Hz, 1H), 7.50 (t, J=1.6 Hz, 1H), 7.63 (dd, J=4.8Hz, J=2.8 Hz, 1H); ESIMS found for C₁₀H₁₀N₂S m/z 191 (M+H).

3-(Furan-3-yl)benzene-1,2-diamine (XLVI): White solid (1.3 g, 7.46 mmol,mmol, 85% yield). ¹H NMR (DMSO-d₆, 400 MHz) δ ppm 4.24 (brs, 2H), 4.57(brs, 2H), 6.46-6.50 (m, 1H), 6.50-6.56 (m, 2H), 6.72 (s, 1H), 7.74 (t,J=1.6 Hz, 1H), 7.87 (s, 1H); ESIMS found for C₁₀H₁₀N₂O m/z 175 (M+H).

Preparation of intermediate (XLIX) is depicted below in Scheme 10.

Step 1

A mixture of 1-methylpiperazine (XLVII) (20 mL) and3-chloro-2-nitroaniline (XXXV) (1.5 g, 8.7 mmol, 1 eq) was stirred at50° C. for 1 h under microwave irradiation. The reaction mixture wasdiluted with water (100 mL) and filtered, the cake washed with water (30mL×3), dried in vacuo to give the3-(4-methylpiperazin-1-yl)-2-nitroaniline (XLVIII) (1.64 g, 6.94 mmol,80% yield) as a yellow solid. ESIMS found for C₁₁H₁₆N₄O₂ m/z 237 (M+H).

Step 2

A mixture of 3-(4-methylpiperazin-1-yl)-2-nitroaniline (XLVIII) (1.64 g,6.9 mmol, 1 eq) and Pd/C (0.2 g) in MeOH (20 mL) was stirred under 30psi of H₂ at room temperature overnight. The reaction was monitored byTLC. The mixture was filtered and the filtrate was concentrated in vacuoto give the 3-(4-methylpiperazin-1-yl)benzene-1,2-diamine (XLIX) (1.31g, 6.35 mmol, 92% yield) as a black solid. ¹H NMR (CDCl₃, 400 MHz) δ ppm2.30 (s, 3H), 3.30 (brs, 2H), 3.68 (brs, 2H), 6.46 (dd, J=7.2 Hz, J=2Hz, 1H), 6.54-6.63 (m, 2H); ESIMS found for C₁₁H₁₈N₄ m/z 207 (M+H).

Preparation of intermediate 3-(piperidin-1-yl)benzene-1,2-diamine (LI)is depicted below in Scheme 11.

Step 1

To a solution of 3-chloro-2-nitroaniline (XXXV) (2.00 g, 11.6 mmol, 1eq) and piperidine (2.95 g, 34.7 mmol, 3 eq) in DMF (60 ml) was addedK₂CO₃ (4.78 g, 34.4 mmol, 3 eq) in one portion and the mixture wasstirred at 120° C. under nitrogen overnight. The reaction mixture wasdiluted with EtOAc (60 ml) and washed with saturated NaHCO₃ solution (50mL). The organic phases were dried over Na₂SO₄ and concentrated invacuo, the resultant residue was purified by silica gel columnchromatography (PE:EtOAc=5:1→1:1) to give2-nitro-3-(piperidin-1-yl)aniline (L) (1.8 g, 8.14 mmol, 70.3% yield) asa black solid. ESIMS found for C₁₁H₁₅N₃O₂ m/z 222 (M+H).

Step 2

A mixture of 2-nitro-3-(piperidin-1-yl)aniline (L) (1.64 g, 6.9 mmol, 1eq) and Pd/C (0.50 g) in MeOH (20 mL) was stirred at room temperatureunder 30 psi H₂ overnight. After the starting material was consumedcompletely, the mixture was filtered through a Celite pad and thefiltrate was concentrated in vacuo to give the3-(piperidin-1-yl)benzene-1,2-diamine (LI) (1.1 g, 5.75 mmol, 76% yield)as a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ ppm 1.59 (brs, 2H), 1.73(quin, J=5.6 Hz, 4H), 2.84 (brs, 4H), 3.50 (brs, 4H), 6.52 (dd, J=6.4Hz, J=1.6 Hz, 1H), 6.59-6.75 (m, 2H); ESIMS found for C₁₁H₁₇N₃ m/z 192(M+H).

Preparation of intermediate 3-(pyridin-4-yl)benzene-1,2-diamine (LVII)is depicted below in Scheme 12.

Step 1

To a solution of 2-bromoaniline (LII) (50 g, 0.29 mol, 1 eq) in aceticanhydride (265 mL) was added dropwise nitric acid (fuming) (36.75 mL,0.93 mol, 3.2 eq) at 0° C. and then stirred at that temperature, whenthe starting material was consumed, the mixture was filtered, thefiltrate was poured into ice water. The aqueous phase was basified withaqueous solution of sodium bicarbonate to pH=7, then the mixture wasextracted with EtOAc (30 mL×3). The organic layers were combined, driedand concentrated in vacuo to give the N-(2-bromo-6-nitrophenyl)acetamide(LIII) (12.6 g, 48.6 mmol, 16.7% yield) as a white solid. ¹H NMR(DMSO-d₆, 400 MHz) δ ppm 2.06 (s, 3H), 7.43 (t, J=8 Hz, 1H), 7.94 (d,J=8 Hz, 1H), 8.05 (d, J=8 Hz, 1H); ESIMS found for C₈H₇BrN₂O₃ m/z 259(M+H).

Step 2

A degassed mixture of N-(2-bromo-6-nitrophenyl)acetamide (LIII) (2.59 g,10 mmol, 1.0 eq),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (LIV) (2.05 g,10 mmol, 1.3 eq), Na₂CO₃ (2.12 g, 20 mmol, 2 eq) and Pd(PPh₃)₄ (1.16 g,1 mmol, 0.1 eq) in a mixed solvent of DME (30 mL) and H₂O (10 mL) washeated to reflux under nitrogen overnight, the mixture was poured ontowater (40 ml) and extracted with EtOAc (30 mL×3). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated in vacuo,purification the resultant residue was purified by column chromatography(EtOAc:PE=1:4→100% EtOAc) to affordN-(2-nitro-6-(pyridin-4-yl)phenyl)acetamide (LV) (1.42 g, 5.52 mmol, 55%yield) as a yellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm 1.92 (s, 3H),7.46 (d, J=5.6 Hz, 2H), 7.69 (t, J=8 Hz, 1H), 7.80 (dd, J=7.6 Hz, J=1.2Hz, 1H), 8.06 (dd, J=8 Hz, J=1.6 Hz, 1H), 8.73 (d, J=6 Hz, 2H), 9.96 (s,1H); ESIMS found for C₁₃H₁₁N₃O₃ m/z 258 (M+H).

Step 3

To a solution of N-(2-nitro-6-(pyridin-4-yl)phenyl)acetamide (LV) (3.94g, 15 mmol, 1 eq) in MeOH (20 mL) was added 2 N aqueous NaOH solution(50 mL) and the mixture was refluxed until the starting material wasconsumed completely, the precipitate was collected by filtration toafford the 2-nitro-6-(pyridin-4-yl)aniline (LVI) (3.0 g, 13.9 mmol, 91%yield) as yellow solid. ESIMS found for C₁₁H₉N₃O₂ m/z 216 (M+H).

Step 4

To a solution of 2-nitro-6-(pyridin-4-yl)aniline (LVI) (3 g, 14 mmol, 1eq) in EtOAc (350 mL) was added Pd/C (0.3 g) and the mixture was stirredat room temperature under 1 atm of H₂ atmosphere overnight, the mixturewas filtered and concentrated in vacuo to give the product3-(pyridin-4-yl)benzene-1,2-diamine (LVII) (2.4 g, 13.0 mmol, 93% yield)as a white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm 4.35 (s, 2H), 4.75 (s,2H), 6.45 (dd, J=7.6 Hz, J=1 Hz, 1H), 6.58 (t, J=7.6 Hz, 1H), 6.67 (d,J=6.8 Hz, 1H), 7.47 (d, J=6 Hz, 2H), 8.65 (d, J=6 Hz, 2H); ESIMS foundfor C₁₁H₁₁N₃ m/z 186 (M+H).

Preparation of intermediate 3-(pyridin-2-yl)benzene-1,2-diamine 3HCl(LXII) is depicted below in Scheme 13.

Scheme 13

To a solution of 2-bromopyridine (LVIII) (10 g, 63 mmol, 1.00 eq) in THF(150 mL) was added n-BuLi (25.3 mL, 63 mmol, 1.00 eq) and the mixturewas stirred at −70° C. for 30 min under nitrogen atmosphere. Thenn-Bu₃SnCl (21.7 g, 67 mmol, 1.06 eq) was added and the mixture wasstirred at the same temperature for another 2 h. Saturated ammoniumchloride solution (150 mL) was added to the solution and extracted withEtOAc (150 mL×3). The combined organic layers were dried over Na₂SO₄,filtered and concentrated in vacuo to afford the crude2-(tributylstannyl)pyridine (LIX) (25.9 g, 63 mmol, 100% yield) as ayellow oil. The crude product was used without further purification.

Step 2

A degassed mixture of N-(2-bromo-6-nitrophenyl)acetamide (LIII) (4.8 g,19 mmol, 1.00 eq), 2-(tributylstannyl)pyridine (LIX) (7.5 g, 20 mmol,1.05 eq) and Pd(PPh₃)₄ (2.1 g, 1.8 mmol, 0.01 eq) in toluene (60 mL) washeated to reflux under nitrogen overnight. Saturated sodium bicarbonatesolution (50 mL) was then added to the mixture and it was extracted withEtOAc (50 mL×3). The combined organic layers were dried over Na₂SO₄,filtered and concentrated in vacuo, the residue was purified by columnchromatography on silica gel (EtOAc:PE=1:2→100% EtOAc) to affordN-(2-nitro-6-(pyridin-2-yl)phenyl)acetamide (LX) (4.4 g, 17.1 mmol, 92%yield) as a white-off solid. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm 1.93 (s,3H), 7.43-7.51 (m, 1H), 7.51-7.65 (m, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.97(dd, J=7.6 Hz, J=2.4 Hz, 3H), 8.75 (d, J=4.4 Hz, 1H), 10.52 (s, 1H);ESIMS found for C₁₃H₁₁N₃O₃ m/z 258 (M+H).

Step 3

To a solution of N-(2-nitro-6-(pyridin-2-yl)phenyl)acetamide (LX) (4.41g, 17 mmol, 1 eq) in MeOH (20 mL) was added 2N NaOH aqueous (50 mL) andthe mixture was refluxed until the stirring material was consumedcompletely. The mixture was concentrated in vacuo to remove the MeOH andthe precipitate was collected by filtration to afford2-nitro-6-(pyridin-2-yl)aniline (LXI) (2.4 g, 11.2 mmol, 65% yield) as ayellow solid. ESIMS found for C₁₁H₉N₃O₂ m/z 216 (M+H).

Step 4

To a solution of 2-nitro-6-(pyridin-2-yl)aniline (LXI) (2.4 g, 0.01mmol, 1 eq) in EtOAc (350 mL) was added Pd/C (1 g) and the mixture wasstirred at room temperature under 1 atm of H₂ atmosphere overnight,filtered and then concentrated in vacuo, to give3-(pyridin-2-yl)benzene-1,2-diamine (1.9 g, 10.3 mmol, 89% yield) as ayellow oil. ESIMS found for C₁₁H₁₁N₃ m/z 186 (M+H).

Step 5

To a solution of 3-(pyridin-2-yl)benzene-1,2-diamine (1.86 g, 0.01 mmol)in EtOAc (200 mL) was added HCl in EtOAc (40 mL) and the mixture wasstirred at 0° C. for 20 min. The precipitate was collected by filtrationto give 3-(pyridin-2-yl)benzene-1,2-diamine-3HCl (LXII) as a yellowsolid. ¹H NMR (DMSO-d₆, 400 MHz) δ ppm 6.89 (t, J=7.6 Hz, 1H), 7.33(brs, 1H), 7.51 (d, J=7.2 Hz, 1H), 7.54-7.66 (m, 2H), 7.97 (d, J=8 Hz,1H), 8.16 (brs, 1H), 8.75 (brs, 1H).

Example 1

Preparation ofN-(5-(3-(4-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide(202) is depicted below in Scheme 14.

Step 1

A solution of N-(5-bromopyridin-3-yl)-2-phenylacetamide (XIV) (2.2 g,5.5 mmol, 1.00 eq),5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbaldehyde(IV) (1.5 g, 5.5 mmol, 1.00 eq), Pd(dppf)Cl₂ (0.28 g, 0.39 mmol, 0.07eq) and Na₂CO₃ (0.8 g, 16.5 mmol, 3.00 eq) in a mixed solvent of1,2-dimethoxyethane (30 mL) and H₂O (5 mL) was refluxed for 3 h undernitrogen atmosphere. The reaction mixture was diluted in water (30 mL)and extracted with EtOAc (20 mL×3). The combined organic layers weredried over Na₂SO₄, filtered and concentrated in vacuo, the resultantresidue was purified by flash chromatography on silica gel(PE/EtOAc=10:1-3:1) to giveN-(5-(3-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide(LXIII) (2.3 g, 4.73 mmol, 51% yield) as a brown oil. ESIMS foundC₂₇H₃₀N₄O₃Si m/z 487 (M+H).

Step 2

To a well stirred solution ofN-(5-(3-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide(LXIII) (100 mg, 0.205 mmol, 1.0 eq),3-(4-methylpiperazin-1-yl)benzene-1,2-diamine (XLIX) (46 mg, 0.223 mmol,1.09 eq) in CH₃CN (2 mL) was added compound2,3,5,6-tetrachlorocyclohexa-2,5-diene-1,4-dione (60 mg, 1.1 eq). Thereaction mixture was refluxed for 3 h, TLC analysis (1:1, PE/EtOAc)showed complete consumption of starting material (LXIII). Theprecipitate was collected by filtration, washed with CH₃CN and driedunder reduced pressure to giveN-(5-(3-(4-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide(LXIV) (41 mg, 0.061 mmol, 29.6% yield). ESIMS found for C₃₈H₄₄N₈O₂Sim/z 673 (M+H).

Step 3

To a well stirred solution ofN-(5-(3-(4-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide(LXIV) (40 mg, 0.06 mmol, 1.0 eq) in DCM (5 mL) was added TFA (0.3 mL)at room temperature for 2 h, TLC analysis (10:1, DCM/MeOH) showedcomplete consumption of compound (LXIV). Then the reaction mixture wasadded NH₄OH (2 mL) and washed with EtOAc and water, dried over Na₂SO₄,filtration, and concentration, the crude product was obtained as asolid, which was purified by preparative HPLC to giveN-(5-(3-(4-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide202 (20 mg, 0.037 mmol, 60.9% yield) as a white solid. ¹H NMR (CD₃OD,400 MHz) δ ppm 2.98 (s, 3H), 3.22-3.31 (m, 2H), 3.51-3.61 (m, 2H),3.67-3.76 (m, 2H), 3.88 (s, 2H), 4.11-4.20 (m, 2H), 7.03 (d, J=7.6 Hz,1H), 7.27-7.51 (m, 7H), 7.91 (ABq, 2H), 8.84 (s, 1H), 8.88 (s, 1H), 8.93(s, 1H), 9.06 (s, 1H); ESIMS found for C₃₂H₃₀N₈O m/z 543.3 (M+H).

The following compounds were prepared in accordance with the proceduredescribed in the above Example 1.

N-(5-(3-(4-(3-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide1

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.29 (t, J=7.2 Hz, 3H), 2.60 (q, J=7.6 Hz,2H), 7.23-7.40 (m, 2H), 7.61-7.77 (m, 5H), 7.94 (d, J=8 Hz, 1H), 7.99(s, 1H), 8.87 (s, 1H), 8.95 (s, 1H), 9.04 (s, 1H), 9.33 (s, 1H); ESIMSfound for C₂₈H₂₁FN₆O m/z 477.2 (M+H).

3-(4-(3-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-5-(pyridin-3-yl)-1H-indazole4

¹H NMR (CD₃OD, 400 MHz) δ ppm 7.32 (t, J=8 Hz, 1H), 7.59-7.73 (m, 4H),7.78 (t, J=7.6 Hz, 1H), 8.02 (d, J=8.4 Hz, 2H), 8.09 (d, J=8.4 Hz, 1H),8.29 (brs, 1H), 8.93 (d, J=5.2 Hz, 2H), 9.18 (d, J=7.6 Hz, 1H), 9.46 (s,1H); ESIMS found for C₂₅H₁₆FN₅ m/z 406.1 (M+H).

3-(4-(3-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-5-(4-methylpyridin-3-yl)-1H-indazole5

¹H NMR (CD₃OD, 400 MHz) δ ppm 2.45 (s, 3H), 7.08 (dt, 1H), 7.36 (t,J=7.6 Hz, 1H), 7.41-7.53 (m, 4H), 7.62 (d, J=8 Hz, 1H), 7.74 (d, J=8.4Hz, 1H), 7.97 (d, 1H), 8.43 (brs, 1H), 8.51 (brs, 1H), 8.60 (s, 1H);ESIMS found for C₂₆H₁₈FN₅ m/z 420.1 (M+H).

5-(3-(4-(3-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)-N,N-dimethylpyridin-3-amine7

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.30 (s, 6H), 7.32 (t, 1H), 7.58-7.68 (m,3H), 7.70 (d, J=7.6 Hz, 1H), 7.78 (t, J=7.6 Hz, 1H), 7.94-8.08 (m, 3H),8.17 (s, 1H), 8.21 (s, 1H), 8.51 (s, 1H), 8.82 (s, 1H); ESIMS found forC₂₇H₂₁FN₆ m/z 449.1 (M+H).

N-(5-(3-(4-(3-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide9

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.31 (d, J=6.8 Hz, 6H), 2.83 (sep, J=6.8Hz, 1H), 7.24-7.33 (m, 1H), 7.62-7.71 (m, 4H), 7.72 (t, J=8 Hz, 1H),7.97 (d, 1H), 8.00 (s, 2H), 8.86 (s, 1H), 9.01 (s, 1H), 9.06 (s, 1H),9.36 (s, 1H); ESIMS found for C₂₉H₂₃FN₆O m/z 491.2 (M+H).

N-(5-(3-(4-(3-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-2-phenylacetamide10

¹H NMR (CD₃OD, 400 MHz) δ ppm 3.89 (s, 2H), 7.22-7.46 (m, 6H), 7.60-7.77(m, 5H), 7.95 (d, J=8 Hz, 1H), 8.00 (s, 2H), 8.81 (s, 1H), 9.01 (s, 1H),9.03 (s, 1H), 9.29 (s, 1H); ESIMS found for C₃₃H₂₃FN₆O m/z 539.1 (M+H).

1-(5-(3-(4-(3-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine13

¹H NMR (CD₃OD, 400 MHz) δ ppm 3.12 (s, 6H), 4.80 (s, 2H), 7.36 (dt,J=8.8 Hz, J=2 Hz, 1H), 7.64-7.77 (m, 4H), 7.83 (t, J=7.2 Hz, 1H), 8.06(d, J=8.8 Hz, 1H), 8.12 (d, J=8 Hz, 1H), 8.20 (d, J=8.4 Hz, 1H), 9.11(s, 1H), 9.41 (s, 1H), 9.51 (s, 1H); ESIMS found for C₂₈H₂₃FN₆ m/z 463.2(M+H).

N-(5-(3-(4-(3-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3,3-dimethylbutanamide16

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.04 (s, 9H), 2.30 (s, 2H), 7.09 (t, J=8Hz, 1H), 7.41-7.52 (m, 3H), 7.57 (d, J=7.6 Hz, 1H), 7.60-7.71 (m, 2H),7.76 (Abq, 2H), 8.69 (s, 1H), 8.71 (s, 1H), 8.83 (brs, 1H), 9.17 (brs,1H); ESIMS found for C₃₁H₂₇FN₆O m/z 519.2 (M+H).

N-(5-(3-(4-(3-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide18

¹H NMR (CD₃OD, 400 MHz) δ ppm 0.90 (t, J=7.2 Hz, 3H), 1.36 (sex, J=7.2Hz, 2H), 1.66 (quin, J=7.6 Hz, 2H), 2.47 (t, J=7.6 Hz, 2H), 7.13-7.22(m, 1H), 7.50-7.59 (m, 4H), 7.63 (t, J=8 Hz, 1H), 7.82-7.93 (m, 3H),8.72 (s, 1H), 8.88 (s, 1H), 8.95 (s, 1H), 9.24 (s, 1H); ESIMS found forC₃₀H₂₅FN₆O m/z 505.2 (M+H).

N-(5-(3-(4-(3-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide19

¹H NMR (DMSO-d₆, 400 MHz) δ ppm 0.95 (d, J=7.6 Hz, 4H), 1.94-2.05 (m,1H), 7.22 (dt, J=6.8 Hz, J=1.6 Hz, 1H), 7.31 (s, 1H), 7.42 (t, J=7.6 Hz,2H), 7.55-7.71 (m, 3H), 7.91 (Abq, 2H), 8.10 (d, J=6.8 Hz, 1H), 8.22 (d,J=10.4 Hz, 1H), 8.92 (s, 1H), 8.97 (s, 1H), 9.02 (s, 1H), 9.17 (s, 1H);ESIMS found for C₂₉H₂₁FN₆O m/z 489.2 (M+H).

N-(5-(3-(4-(3-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide21

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.66-1.78 (m, 2H), 1.78-1.89 (m, 2H),1.89-2.01 (m, 2H), 2.01-2.12 (m, 2H), 3.01 (quin, J=8 Hz, 1H), 7.26-7.35(m, 1H), 7.62-7.73 (m, 4H), 7.76 (t, J=8 Hz, 1H), 7.98 (d, J=8 Hz, 1H),8.02 (s, 2H), 8.83 (s, 1H), 9.03 (s, 1H), 9.05 (s, 1H), 9.35 (d, J=1.6Hz, 1H); ESIMS found for C₃₁H₂₅FN₆O m/z 517.2 (M+H).

N-(5-(3-(4-(3-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide22

¹H NMR (DMSO-d₆, 400 MHz) δ ppm 1.27 (d, J=14.8 Hz, 1H), 1.38 (q, J=13.6Hz, 2H), 1.54 (q, J=10.4 Hz, 2H), 1.72 (d, J=12.4 Hz, 1H), 1.84 (d,J=13.6 Hz, 2H), 1.94 (d, J=12.4 Hz, 2H), 2.49 (q, J=10.8 Hz, 1H),7.18-7.28 (m, 1H), 7.54-7.64 (m, 4H), 7.68 (t, J=8 Hz, 1H), 7.90 (d, J=8Hz, 1H), 7.95 (s, 2H), 8.76 (s, 1H), 8.94 (s, 1H), 8.97 (s, 1H), 9.27(s, 1H); ESIMS found for C₃₂H₂₇FN₆O m/z 531.2 (M+H).

N-(5-(3-(4-(4-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide26

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.08 (d, J=6.4 Hz, 6H), 2.28 (non, J=6.8Hz, 1H), 2.45 (d, J=7.2 Hz, 2H), 7.39 (t, J=8.4 Hz, 1H), 7.64 (d, 1H),7.72 (t, 1H), 7.87 (dd, J=8.4 Hz, J=5.2 Hz, 2H), 7.94 (d, 1H), 8.00 (s,2H), 8.84 (s, 1H), 9.02 (s, 1H), 9.06 (s, 1H), 9.32 (s, 1H); ESIMS foundfor C₃₀H₂₅FN₆O m/z 5051 (M+H).

3-(4-(4-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-5-(4-methylpyridin-3-yl)-1H-indazole29

¹H NMR (CD₃OD, 400 MHz) δ ppm 2.69 (s, 3H), 7.30-7.42 (m, 2H), 7.63 (d,J=6 Hz, 1H), 7.69-7.87 (m, 4H), 7.94-8.06 (m, 2H), 8.14 (brs, 1H), 8.56(brrs, 1H), 8.80 (brs, 1H), 8.92 (brs, 1H); ESIMS found for C₂₆H₁₈FN₅m/z 420.2 (M+H).

N-(5-(3-(4-(4-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide32

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.42 (s, 9H), 7.39 (t, J=8.4 Hz, 2H), 7.65(d, J=7.2 Hz, 1H), 7.74 (t, J=7.6 Hz, 1H), 7.80-7.91 (m, 2H), 7.98 (d,J=8 Hz, 1H), 8.02 (s, 2H), 8.87 (s, 1H), 9.10 (s, 1H), 9.26 (s, 1H),9.39 (s, 1H); ESIMS found for C₃₀H₂₅FN₆O m/z 505.2 (M+H).

N-(5-(3-(4-(4-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide33

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.29 (d, J=6.8 Hz, 6H), 2.79 (sep, J=6.8Hz, 1H), 7.37 (t, J=8.8 Hz, 2H), 7.62 (d, J=7.2 Hz, 1H), 7.70 (t, 1H),7.82-7.93 (m, 3H), 7.98 (s, 2H), 8.78 (s, 1H), 8.98 (s, 1H), 9.00 (s,1H), 9.23 (s, 1H); ESIMS found for C₂₉H₂₃FN₆O m/z 491.2 (M+H).

N-(5-(3-(4-(4-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide35

¹H NMR (CD₃OD, 400 MHz) δ ppm 7.43 (t, 2H), 7.61-7.82 (m, 5H), 7.92 (dd,2H), 8.00 (d, 1H), 8.08 (Abq, J=5.6 Hz, 2H), 8.16 (d, J=7.6 Hz, 2H),8.89 (s, 1H), 9.13 (s, 1H), 9.34 (s, 1H), 9.47 (s, 1H); ESIMS found forC₃₂H₂₁FN₆O m/z 525.1 (M+H).

3-(4-(4-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole38

¹H NMR (CD₃OD, 400 MHz) δ ppm 2.14 (brs, 2H), 2.26 (brs, 2H), 3.35 (brs,4H), 3.70 (brs, 2H), 7.36 (t, J=8 Hz, 2H), 7.62 (d, J=7.2 Hz, 1H), 7.72(t, 1H), 7.82 (brs, 2H), 7.98 (d, J=8.4 Hz, 1H), 8.03 (d, J=8 Hz, 1H),8.12 (d, J=8.4 Hz, 1H), 9.02 (s, 1H), 9.03 (s, 1H), 9.32 (s, 1H), 9.38(s, 1H); ESIMS found for C₃₀H₂₅FN₆ m/z 489.2 (M+H).

N-(5-(3-(4-(4-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide41

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.12 (t, J=7.2 Hz, 3H), 1.87 (sex, J=7.6Hz, 2H), 2.62 (t, J=7.6 Hz, 2H), 7.45 (t, J=8.4 Hz, 2H), 7.73 (dd, J=6.8Hz, J=1 Hz, 1H), 7.81 (t, J=8 Hz, 1H), 7.90 (dd, J=8.4 Hz, J=5.2 Hz,2H), 8.02 (d, J=7.6 Hz, 1H), 8.07 (d, J=1 Hz, 2H), 8.87 (s, 1H), 9.11(s, 1H), 9.12 (s, 1H), 9.37 (d, J=1.6 Hz, 1H); ESIMS found forC₂₉H₂₃FN₆O m/z 491.2 (M+H).

N-(5-(3-(4-(4-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide42

¹H NMR (DMSO-d₆, 400 MHz) δ ppm 0.92 (t, J=7.2 Hz, 3H), 1.38 (sex, J=7.6Hz, 2H), 1.66 (quin, J=7.6 Hz, 2H), 2.72 (d, J=5.2 Hz, 2H), 7.34-7.46(m, 3H), 7.50 (d, J=7.6 Hz, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.90 (s, 2H),8.29 (brs, 2H), 8.93 (s, 1H), 8.96 (s, 1H), 9.03 (s, 1H), 9.19 (s, 1H);ESIMS found for C₃₀H₂₅FN₆O m/z 505.2 (M+H).

N-(5-(3-(4-(4-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide43

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.43 (d, J=7.2 Hz, 2H), 1.50 (brs, 2H),1.59 (t, J=7.2 Hz, 1H), 7.78 (t, 2H), 8.03 (d, J=7.2 Hz, 1H), 8.11 (d,J=7.6 Hz, 1H), 8.14 (brs, 2H), 8.35 (d, J=7.6 Hz, 1H), 8.40 (s, 2H),9.24 (s, 1H), 9.42 (brs, 2H), 9.69 (s, 1H); ESIMS found for C₂₉H₂₁FN₆Om/z 489.2 (M+H).

N-(5-(3-(4-(4-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide44

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.92-2.02 (m, 1H), 2.07-2.19 (m, 1H),2.28-2.39 (m, 2H), 2.39-2.51 (m, 2H), 3.42-3.53 (m, 1H), 7.40 (t, J=8.4Hz, 2H), 7.67 (d, J=7.6 Hz, 1H), 7.77 (t, J=8 Hz, 1H), 7.85 (Abq, J=8Hz, J=4.8 Hz, 2H), 8.01 (d, J=8 Hz, 1H), 8.03 (s, 2H), 8.87 (s, 1H),9.10 (s, 2H), 9.38 (s, 1H); ESIMS found for C₃₀H₂₃FN₆O m/z 503.2 (M+H).

N-(5-(3-(4-(4-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide45

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.64-1.76 (m, 2H), 1.76-1.87 (m, 2H),1.87-1.97 (m, 2H), 1.97-2.11 (m, 2H), 3.00 (quin, J=8 Hz, 1H), 7.36 (t,J=8.4 Hz, 2H), 7.61 (d, J=7.6 Hz, 1H), 7.69 (t, 1H), 7.86 (Abq, J=8 Hz,J=5.2 Hz, 2H), 7.91 (d, J=8 Hz, 1H), 7.97 (s, 2H), 8.80 (s, 1H), 9.00(s, 2H), 9.26 (s, 1H); ESIMS found for C₃₁H₂₅FN₆O m/z 517.2 (M+H).

N-(5-(3-(4-(4-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide46

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.44 (q, J=12.8 Hz, 2H), 1.62 (q, J=14.8Hz, 2H), 1.90 (d, J=12.8 Hz, 2H), 2.01 (d, J=16 Hz, 2H), 2.50-2.68 (m,1H), 7.39 (t, J=8.8 Hz, 2H), 7.62 (d, 1H), 7.67 (t, 1H), 7.90 (t, 3H),7.98 (s, 2H), 8.80 (s, 1H), 8.97 (s, 1H), 8.99 (s, 1H), 9.21 (s, 1H);ESIMS found for C₃₂H₂₇FN₆O m/z 531.2 (M+H).

N-benzyl-1-(5-(3-(4-(4-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine47

¹H NMR (CD₃OD, 400 MHz) δ ppm 4.47 (s, 2H), 4.64 (s, 2H), 7.38 (t, J=8.8Hz, 2H), 7.48-7.53 (m, 3H), 7.62-7.69 (m, 3H), 7.76 (t, J=7.6 Hz, 1H),7.85 (Abq, J=8.4 Hz, J=5.2 Hz, 2H), 8.02 (Abq, J=10.8 Hz, J=8.8 Hz, 2H),8.09 (d, J=8.8 Hz, 1H), 8.96 (brs, 1H), 8.97 (s, 1H), 9.21 (s, 1H), 9.36(brs, 1H); ESIMS found for C₃₃H₂₅FN₆ m/z 525.2 (M+H).

N-((5-(3-(4-(2-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)ethanamine54

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.49 (t, J=7.2 Hz, 3H), 3.29-3.38 (m, 2H),4.62 (s, 2H), 7.36-7.49 (m, 2H), 7.57-7.73 (m, 3H), 7.79 (t, J=8 Hz,1H), 8.02 (d, J=8.8 Hz, 1H), 8.14 (d, J=7.6 Hz, 2H), 9.05 (s, 1H), 9.08(s, 1H), 9.41 (s, 1H), 9.45 (s, 1H); ESIMS found for C₂₈H₂₃FN₆ m/z 463.2(M+H).

N-(5-(3-(4-(2-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide57

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.30 (d, J=6.8 Hz, 6H), 2.84 (sep, J=7.2Hz, 1H), 7.36-7.49 (m, 2H), 7.61 (q, J=7.2 Hz, 1H), 6.65 (d, 7.6 Hz,1H), 7.71 (t, J=7.6 Hz, 1H), 7.77 (t, J=7.6 Hz, 1H), 8.00 (s, 2H), 8.05(d, J=8 Hz, 1H), 8.85 (s, 1H), 9.02 (s, 1H), 9.08 (brs, 1H), 9.36 (br,1H); ESIMS found for C₂₉H₂₃FN₆O m/z 491.2 (M+H).

N-(5-(3-(4-(2-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide59

¹H NMR (CD₃OD, 400 MHz) δ ppm 7.36-7.47 (m, 2H), 7.56-7.65 (m, 3H),7.65-7.76 (m, 3H), 7.78 (t, 1H), 8.00-8.11 (m, 2H), 8.13 (d, J=7.6 Hz,3H), 8.91 (s, 1H), 9.18 (s, 1H), 9.34 (s, 1H), 9.53 (s, 1H); ESIMS foundfor C₃₂H₂₁FN₆O m/z 525.2 (M+H).

5-(3-(4-(2-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)-N-isopropylpyridin-3-amine60

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.23 (d, J=5.6 Hz, 6H), 3.78 (sep, J=5.6Hz, 1H), 7.22-7.35 (m, 2H), 7.49 (q, J=6.8 Hz, 1H), 7.53 (d, J=7.2 Hz,1H), 7.59 (t, J=7.6 Hz, 1H), 7.67 (t, J=8 Hz, 1H), 7.83 (s, 2H), 7.93(d, J=8 Hz, 3H), 8.30 (s, 1H), 8.65 (s, 1H); ESIMS found for C₂₈H₂₃FN₆m/z 463.1 (M+H).

3-(4-(2-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole63

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.61 (brs, 1H), 1.83-2.07 (m, 5H), 2.17(s, 1H), 2.69 (s, 1H), 3.13-3.29 (m, 2H), 3.65 (d, J=9.6 Hz, 2H), 7.42(quin, J=8.8 Hz, 2H), 7.61 (q, J=6.8 Hz, 1H), 7.69 (q, J=8.4 Hz, 2H),7.79 (t, J=8 Hz, 1H), H), 8.01 (d, J=8.4 Hz, 1H), 8.16 (t, J=7.6 Hz,2H), 9.10 (s, 1H), 9.48 (s, 1H); ESIMS found for C₃₁H₂₇FN₆ m/z 503.2(M+H).

N-(5-(3-(4-(2-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide66

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.02 (t, J=7.6 Hz, 3H), 1.48 (sex, J=7.2Hz, 2H), 1.77 (quin, J=7.6 Hz, 2H), 2.51 (t, J=8 Hz, 2H), 7.37 (quin,J=8.4 Hz, 3H), 7.46 (sex, J=7.6 Hz, 3H), 7.77-7.89 (m, 4H), 8.53 (s,1H), 8.74 (s, 1H), 8.79 (s, 1H), 8.85 (s, 1H); ESIMS found forC₃₀H₂₅FN₆O m/z 505.2 (M+H).

N-(5-(3-(4-(2-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide69

¹H NMR (DMSO-d₆, 400 MHz) δ ppm 1.57-1.69 (m, 2H), 1.66-1.76 (m, 2H),1.73-1.86 (m, 2H), 1.90-2.02 (m, 2H), 2.95 (quin, J=8 Hz, 1H), 7.34-7.55(m, 5H), 7.76 (brd, J=7.2 Hz, 1H), 7.82-8.00 (m, 3H), 8.78 (s, 1H), 8.84(s, 1H), 8.92 (s, 1H), 9.09 (s, 1H); ESIMS found for C₃₁H₂₅FN₆O m/z517.2 (M+H).

1-Cyclopentyl-N-((5-(3-(4-(2-fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)methanamine72

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.16-1.36 (m, 4H), 1.51-1.70 (m, 4H), 1.88(brs, 2H), 2.80 (s, 1H), 3.10-3.17 (m, 2H), 7.23-7.36 (m, 2H), 7.45-7.55(m, 1H), 7.54-7.64 (m, 2H), 7.64-7.73 (m, 1H), 7.92 (d, J=8 Hz, 1H),8.04 (d, J=7.6 Hz, 2H), 9.00 (brs, 2H), 9.37 (brs, 1H), 9.43 (brs, 1H);ESIMS found for C₃₂H₂₉FN₆ m/z 517.2 (M+H).

5-(3-(4-(Pyridin-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-amine75

¹H NMR (CD₃OD, 400 MHz) δ ppm 7.63 (t, J=8 Hz, 1H), 7.77 (d, J=7.6 Hz,1H), 7.88 (s, 2H), 7.93 (d, J=8 Hz, 1H), 8.05 (d, J=2.4 Hz, 1H), 8.11(s, 1H), 3.00 (dd, J=8 Hz, 1H), 8.45 (s, 1H), 8.88 (s, 1H), 8.94 (d,J=5.6 Hz, 1H), 9.36 (d, J=8 Hz, 1H), 9.73 (s, 1H); ESIMS found forC₂₄H₁₇N₇ m/z 404.1 (M+H).

5-(4-Methylpyridin-3-yl)-3-(4-(pyridin-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazole77

¹H NMR (CD₃OD, 400 MHz) δ ppm 2.68 (s, 3H), 7.71 (d, J=8.8 Hz, 1H), 7.81(Abq, J=6.8 Hz, J=4 Hz, 2H), 7.97 (d, J=8.8 Hz, 1H), 8.11-8.31 (m, 2H),8.32 (dd, 1H), 8.69 (s, 1H), 8.78 (d, J=6.4 Hz, 1H), 8.92 (s, 1H), 9.01(d, J=6 Hz, 1H), 9.11 (d, 1H), 9.50 (s, 1H); ESIMS found for C₂₅H₁₈N₆m/z 403.2 (M+H).

N,N-Dimethyl-5-(3-(4-(pyridin-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-amine79

¹H NMR (CD₃OD, 400 MHz) δ ppm 3.10 (s, 6H), 7.42 (t, J=8 Hz, 1H), 7.49(d, J=7.2 Hz, 1H), 7.52 (s, 1H), 7.61 (dd, J=8 Hz, J=3.2 Hz, 1H), 7.67(d, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.79 (d, 1H), 8.07 (d, 1H), 8.23 (s,1H), 8.30 (s, 1H), 8.57 (d, J=3.6 Hz, 1H), 8.61 (brs, 1H), 8.82 (s, 1H),9.25 (brs, 1H); ESIMS found for C₂₆H₂₁N₇ m/z 432.2 (M+H).

N-Isopropyl-5-(3-(4-(pyridin-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-amine84

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.34 (d, J=6.4 Hz, 6H), 3.88 (sep, J=6.4Hz, 1H), 7.68 (t, J=7.6 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.91 (s, 2H),7.99 (d, J=8.4 Hz, 1H), 8.02-8.07 (m, 2H), 8.32 (dd, J=8 Hz, J=5.6 Hz,1H), 8.46 (s, 1H), 8.91 (s, 1H), 8.98 (d, J=5.6 Hz, 1H), 9.28 (d, J=8.4Hz, 1H), 9.70 (s, 1H); ESIMS found for C₂₇H₂₃N₇ m/z 446.2 (M+H).

3,3-Dimethyl-N-(5-(3-(4-(pyridin-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide88

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.19 (s, 9H), 2.36 (s, 2H), 7.41 (t, J=7.6Hz, 1H), 7.50 (d, J=7.2 Hz, 1H), 7.65 (quin, J=5.2 Hz, 2H), 7.76 (q,J=6.8 Hz, 2H), 8.22 (brs, 2H), 8.41 (s, 1H), 8.55 (d, J=4.4 Hz, 1H),8.65 (s, 1H), 8.67 (brs, 1H), 8.82 (s, 1H), 8.85 (s, 1H), 9.31 (brs,1H); ESIMS found for C₃₀H₂₇N₇O m/z 502.2 (M+H).

N-(5-(3-(4-(Pyridin-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide89

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.09 (t, J=7.6 Hz, 3H), 1.84 (sex, J=7.2Hz, 2H), 2.59 (t, J=7.6 Hz, 2H), 7.64 (t, J=8 Hz, 1H), 7.81 (d, J=7.2Hz, 1H), 7.88-7.99 (m, 3H), 8.33 (dd, J=8 Hz, J=5.6 Hz, 1H), 8.94 (d,J=5.6 Hz, 1H), 8.98 (s, 1H), 9.08 (t, J=1.8 Hz, 2H), 9.29 (d, J=1.6 Hz,1H), 9.36 (d, J=8.4 Hz, 1H), 9.90 (s, 1H); ESIMS found for C₂₈H₂₃N₇O m/z474.1 (M+H).

N-(5-(3-(4-(Pyridin-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide90

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.02 (t, J=7.6 Hz, 3H), 1.48 (sex, J=7.6Hz, 2H), 1.77 (quin, J=7.2 Hz, 2H), 2.61 (t, J=7.6 Hz, 2H), 7.83 (d, J=6Hz, 2H), 8.00 (s, 2H), 8.14 (d, J=6 Hz, 1H), 8.38 (t, J=7.2 Hz, 1H),9.05 (t, J=7.6 Hz, 3H), 9.14 (d, J=7.6 Hz, 1H), 9.18 (s, 1H), 9.43 (s,1H), 9.57 (s, 1H); ESIMS found for C₂₉H₂₅N₇O m/z 488.1 (M+H).

N-(5-(3-(4-(Pyridin-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide92

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.86-1.98 (m, 1H), 2.06 (sex, J=9.6 Hz,1H), 2.19-2.31 (m, 2H), 2.38 (quin, J=9.2 Hz, 2H), 3.34 (quin, J=8.4 Hz,1H), 7.31 (t, J=8 Hz, 1H), 7.41 (d, J=7.2 Hz, 1H), 7.52-7.60 (m, 1H),7.60 (d, J=8.4 Hz, 1H), 7.66 (d, J=8.4 Hz, 1H), 8.12 (s, 1H), 8.35 (s,1H), 8.47 (d, J=4.8 Hz, 1H), 8.53 (s, 1H), 8.61 (d, J=7.6 Hz, 1H), 8.69(s, 1H), 8.76 (s, 1H), 9.25 (s, 1H); ESIMS found for C₂₉H₂₃N₇O m/z 486.2(M+H).

N-(5-(3-(4-(Pyridin-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide94

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.45 (q, J=12.8 Hz, 2H), 1.61 (q, J=13.2Hz, 2H), 1.79 (d, J=12.8 Hz, 1H), 1.91 (d, J=12.8 Hz, 2H), 2.03 (d,J=11.6 Hz, 2H), 2.60 (t, J=11.2 Hz, 1H), 2.77 (d, J=4.4 Hz, 1H), 7.71(t, J=7.6 Hz, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.97 (s, 2H), 8.01 (d, J=8Hz, 1H), 8.35 (t, J=6.4 Hz, 1H), 8.97 (d, J=5.2 Hz, 1H), 9.01 (s, 1H),9.08 (s, 1H), 9.11 (s, 1H), 9.29 (d, J=8 Hz, 1H), 9.36 (s, 1H), 9.78 (s,1H); ESIMS found for C₃₁H₂₇N₇O m/z 514.3 (M+H).

N-Benzyl-1-(5-(3-(4-(pyridin-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine95

¹H NMR (CD₃OD, 400 MHz) δ ppm 4.39 (s, 2H), 4.62 (s, 2H), 7.34-7.42 (m,3H), 7.58 (t, J=4.4 Hz, 2H), 7.62 (t, J=7.6 Hz, 1H), 7.71 (d, J=7.6 Hz,1H), 7.85 (d, J=8.8 Hz, 1H), 7.96 (t, J=7.2 Hz, 2H), 8.21 (t, 1H), 8.85(d, J=4.4 Hz, 1H), 8.93 (brs, 1H), 9.04 (s, 1H), 9.11 (s, 1H), 9.36 (s,1H), 9.37 (brs, 1H), 9.65 (s, 1H); ESIMS found for C₃₂H₂₅N₇ m/z 508.2(M+H).

N-(5-(3-(4-(Pyridin-4-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide104

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.42 (s, 9H), 7.72 (t, J=8 Hz, 1H),7.92-8.00 (m, 3H), 8.07 (d, J=8 Hz, 1H), 8.95 (d, J=5.6 Hz, 2H), 9.02(s, 1H), 9.06 (d, J=6 Hz, 2H), 9.12 (s, 1H), 9.28 (s, 1H), 9.41 (s, 1H);ESIMS found for C₂₉H₂₅N₇O m/z 488.1 (M+H).

2-Phenyl-N-(5-(3-(4-(pyridin-4-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide106

¹H NMR (CD₃OD, 400 MHz) δ ppm 3.92 (s, 2H), 7.25-7.45 (m, 6H), 7.59 (t,1H), 7.87-7.98 (m, 4H), 8.92 (d, J=6.4 Hz, 2H), 8.98 (s, 1H), 9.03 (s,1H), 9.12 (s, 2H), 9.15 (d, J=5.2 Hz, 1H); ESIMS found for C₃₂H₂₃N₇O m/z522.1 (M+H).

N-Isopropyl-5-(3-(4-(pyridin-4-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-amindazole108

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.23 (d, J=6H), 3.78 (sep, J=6 Hz, 1H),7.68 (t, J=8 Hz, 1H), 7.79-7.87 (m, 3H), 7.93 (s, 1H), 7.98 (s, 1H),8.03 (d, J=8 Hz, 1H), 8.36 (s, 1H), 8.67 (d, J=6.4 Hz, 2H), 8.83 (s,1H), 8.96 (d, J=6 Hz, 2H); ESIMS found for C₂₇H₂₃N₇ m/z 446.3 (M+H).

3-(4-(Pyridin-4-yl)-1H-benzo[d]imidazol-2-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole110

¹H NMR (CD₃OD, 400 MHz) δ ppm 2.04-2.32 (m, 6H), 3.64 (brs, 2H), 4.67(s, 2H), 7.56 (t, J=7.6 Hz, 1H), 7.82-8.01 (m, 4H), 8.72 (s, 1H), 8.87(brs, 1H), 8.96 (d, J=6.8 Hz, 2H), 9.00 (s, 1H), 9.15 (d, J=6 Hz, 2H),9.27 (brs, 1H); ESIMS found for C₂₉H₂₅N₇ m/z 472.1 (M+H).

N-(5-(3-(4-(Pyridin-4-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide114

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.00 (t, J=7.2 Hz, 3H), 1.47 (sex, J=7.2Hz, 2H), 1.76 (quin, J=7.6 Hz, 2H), 2.58 (t, J=8 Hz, 2H), 7.58 (t, J=7.6Hz, 1H), 7.86-7.98 (m, 4H), 8.97 (s, 1H), 8.98 (d, J=6.4 Hz, 2H), 9.01(s, 1H), 9.05 (s, 1H), 9.14 (d, J=6.4 Hz, 2H), 9.22 (s, 1H); ESIMS foundfor C₂₉H₂₅N₇O m/z 488.1 (M+H).

N-(5-(3-(4-(Pyridin-4-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide116

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.92-2.04 (m, 1H), 2.12 (sex, 1H),2.27-2.37 (m, 2H), 2.43 (quin, 2H), 3.50 (quin, 1H), 7.81 (t, 1H), 7.94(d, 1H), 7.99 (s, 2H), 8.16 (d, 1H), 8.75 (d, 2H), 9.01 (s, 1H), 9.06(s, 1H), 9.10 (d, 2H), 9.12 (s, 1H), 9.41 (s, 1H); ESIMS found forC₂₉H₂₃N₇O m/z 486.2 (M+H).

N-(5-(3-(4-(Pyridin-4-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide117

¹H NMR (DMSO-d₆, 400 MHz) δ ppm 1.53-1.64 (m, 2H), 1.64-1.73 (m, 2H),1.73-1.84 (m, 2H), 1.86-2.01 (m, 2H), 2.91 (quin, J=7.6 Hz, 1H), 7.47(t, J=7.6 Hz, 1H), 7.75 (d, J=8 Hz, 1H), 7.85 (s, 3H), 8.65 (s, 1H),8.75 (s, 1H), 8.79 (s, 1H), 8.83 (s, 4H), 8.90 (s, 1H), 10.38 (s, 1H);ESIMS found for C₃₀H₂₅N₇O m/z 500.1 (M+H).

N-(5-(3-(4-(Pyridin-4-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide118

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.25-1.50 (m, 3H), 1.58 (q, J=14.4 Hz,2H), 1.76 (d, J=12.4 Hz, 1H), 1.88 (d, J=12.8 Hz, 2H), 1.98 (d, J=12 Hz,2H), 2.50 (quin, 1H), 7.53 (t, J=8 Hz, 1H), 7.78-7.89 (m, 3H), 7.93 (d,J=7.6 Hz, 1H), 8.82 (s, 2H), 8.88 (s, 1H), 8.93 (d, J=6 Hz, 3H), 9.16(d, J=6 Hz, 2H); ESIMS found for C₃₁H₂₇N₇O m/z 514.2 (M+H).

3-Methyl-N-(5-(3-(4-(pyridin-2-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide122

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.09 (d, J=6.8 Hz, 6H), 2.27 (non, J=6.8Hz, 1H), 2.45 (d, J=7.6 Hz, 2H), 7.64 (t, J=8 Hz, 1H), 7.89 (q, J=8.8Hz, 2H), 7.98 (d, J=8 Hz, 1H), 8.05 (brs, 1H), 8.10 (d, J=7.6 Hz, 1H),8.68-8.79 (m, 2H), 8.96 (s, 1H), 9.08 (s, 1H), 9.16 (s, 2H), 9.33 (s,1H); ESIMS found for C₂₉H₂₅N₇O m/z 488.2 (M+H).

5-(4-Methylpyridin-3-yl)-3-(4-(pyridin-2-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazole125

¹H NMR (CD₃OD, 400 MHz) δ ppm 2.72 (s, 3H), 7.69-7.81 (m, 2H), 7.96 (d,J=8 Hz, 1H), 8.06 (d, J=6.8 Hz, 1H), 8.08-8.22 (m, 3H), 8.66 (brs, 1H),8.70-8.80 (m, 3H), 9.01 (s, 1H), 9.05 (brs, 1H); ESIMS found forC₂₅H₁₈N₆ m/z 403.1 (M+H).

N,N-Dimethyl-5-(3-(4-(pyridin-2-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-amine127

¹H NMR (CD₃OD, 400 MHz) δ ppm 2.68 (s, 3H), 2.92 (s, 3H), 7.68 (t, 1H),7.90 (d, J=8.8 Hz, 1H), 7.99 (d, 1H), 8.00-8.10 (m, 2H), 8.10-8.23 (m,2H), 8.60 (s, 1H), 8.69 (t, J=8 Hz, 1H), 8.78 (d, J=8.4 Hz, 1H), 8.99(s, 1H), 9.06 (d, J=4.8 Hz, 1H); ESIMS found for C₂₆H₂₁N₇ m/z 432.3(M+H).

N-(5-(3-(4-(Pyridin-2-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide129

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.32 (d, J=6.8 Hz, 6H), 2.85 (sep, J=6.8Hz, 1H), 7.63 (t, J=8 Hz, 1H), 7.91 (q, J=8.8 Hz, 2H), 7.97 (d, J=8 Hz,1H), 8.04 (brs, 1H), 8.12 (d, J=7.2 Hz, 1H), 8.71 (t, J=7.2 Hz, 1H),8.78 (d, J=8 Hz, 1H), 8.97 (s, 1H), 9.15 (s, 2H), 9.32 (s, 1H); ESIMSfound for C₂₈H₂₃N₇O m/z 474.1 (M+H).

N,N-Dimethyl-1-(5-(3-(4-(pyridin-2-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine133

¹H NMR (CD₃OD, 400 MHz) δ ppm 3.11 (brs, 6H), 4.87 (brs, 2H), 7.50 (brs,1H), 7.72 (brs, 1H), 7.84 (brs, 2H), 7.99 (brs, 1H), 8.06 (brs, 1H),8.52 (brs, 1H), 8.66 (brs, 1H), 8.96 (brs, 1H), 9.10 (brs, 1H), 9.15(brs, 1H), 9.60 (brs, 1H), 9.64 (brs, 1H); ESIMS found for C₂₇H₂₃N₇ m/z446.1 (M+H).

3-(4-(Pyridin-2-yl)-1H-benzo[d]imidazol-2-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole134

¹H NMR (DMSO-d₆, 400 MHz) δ ppm 1.92 (brs, 2H), 2.07 (brs, 2H), 3.23(brs, 2H), 3.48 (brs, 2H), 4.74 (brs, 2H), 7.53 (brs, 1H), 7.88 (brs,2H), 8.02 (brs, 1H), 8.14 (brs, 2H), 8.75 (brs, 1H), 9.04 (brs, 1H),9.12 (s, 1H), 9.17 (brs, 1H), 9.20 (brs, 1H), 9.41 (s, 1H), 9.60 (s,1H), 12.01 (brs, 1H); ESIMS found for C₂₉H₂₅N₇ m/z 472.2 (M+H).

N-(5-(3-(4-(Pyridin-2-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide138

¹H NMR (DMSO-d₆, 400 MHz) δ ppm 0.94 (t, J=7.2 Hz, 3H), 1.20 (sex, J=7.2Hz, 2H), 1.39 (quin, J=7.6 Hz, 2H), 2.52 (t, J=8 Hz, 2H), 7.21-7.42 (m,2H), 7.56 (t, J=7.6 Hz, 1H), 7.65-7.98 (m, 4H), 8.16 (d, J=8 Hz, 1H),8.62 (d, J=8.8 Hz, 1H), 8.95 (s, 1H), 9.01 (s, 1H), 9.03-9.17 (m, 2H);ESIMS found for C₂₉H₂₅N₇O m/z 488.2 (M+H).

N-(5-(3-(4-(Pyridin-2-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide140

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.92-2.05 (m, 1H), 2.05-2.20 (m, 1H),2.26-2.40 (m, 2H), 2.37-2.51 (m, 2H), 3.46 (quin, J=8.4 Hz, 1H), 7.55(t, J=7.2 Hz, 1H), 7.72 (d, J=8 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.87(d, J=8 Hz, 1H), 7.96 (d, J=8 Hz, 1H), 8.06 (brs, 1H), 8.62 (d, J=7.6Hz, 1H), 8.71 (brs, 1H), 8.80 (s, 1H), 8.98 (s, 1H), 9.10 (s, 2H), 9.28(s, 1H); ESIMS found for C₂₉H₂₃N₇O m/z 486.2 (M+H).

N-(5-(3-(4-(Pyridin-2-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide142

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.37-1.66 (m, 3H), 1.38 (d, J=12.4 Hz,1H), 1.90 (d, J=12.8 Hz, 2H), 2.02 (d, J=11.2 Hz, 2H), 2.59 (s, 1H),7.65 (t, J=8 Hz, 1H), 7.95 (s, 2H), 8.00 (d, J=7.6 Hz, 2H), 8.21 (d,J=7.5 Hz, 1H), 8.70 (t, J=7.6 Hz, 1H), 8.87 (d, J=8.4 Hz, 1H), 9.02 (s,1H), 9.11 (s, 1H), 9.13-9.20 (m, 2H), 9.25 (s, 1H); ESIMS found forC₃₁H₂₇N₇O m/z 514.3 (M+H).

1-Cyclopentyl-N-((5-(3-(4-(pyridin-2-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)methanamine144

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.44 (brs, 2H), 1.68 (brs, 2H), 1.77 (brs,2H), 2.01 (brs, 2H), 2.45 (brs, 1H), 3.30 (brs, 2H), 7.58 (brs, 1H),7.86 (d, J=6 Hz, 1H), 7.96 (d, J=6.8 Hz, 1H), 8.05 (brs, 3H), 8.69 (brs,2H), 9.13 (brs, 3H), 9.59 (brs, 1H), 9.61 (brs, 1H); ESIMS found forC₃₁H₂₉N₇ m/z 500.2 (M+H).

3-Methyl-N-(5-(3-(4-(piperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide146

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.08 (d, J=6.8 Hz, 6H), 1.90 (brs, 2H),2.16-2.33 (m, 5H), 2.44 (d, J=7.6 Hz, 2H), 4.21 (brs, 4H), 7.47 (t, J=8Hz, 1H), 7.56 (d, J=8 Hz, 1H), 7.80 (d, J=8 Hz, 1H), 7.93 (s, 2H), 9.03(s, 2H), 9.10 (s, 1H), 9.26 (s, 1H); ESIMS found for C₂₉H₃₁N₇O m/z 494.3(M+H).

N,N-Dimethyl-5-(3-(4-(piperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-amine151

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.80 (brs, 2H), 2.10 (brs, 4H), 3.16 (s,6H), 4.07 (brs, 4H), 7.22-7.29 (m, 1H), 7.31-7.41 (m, 1H), 7.47 (d, J=8Hz, 1H), 7.68 (d, 1H), 7.78 (d, 1H), 8.01 (s, 1H), 8.10 (s, 1H), 8.38(s, 1H), 8.87 (s, 1H); ESIMS found for C₂₆H₂₇N₇ m/z 438.2 (M+H).

N-(5-(3-(4-(Piperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide155

¹H NMR (DMSO-d₆, 400 MHz) δ ppm 1.79 (brs, 2H), 2.17 (brs, 4H), 4.16(brs, 4H), 7.46 (t, J=8 Hz, 1H), 7.52-7.63 (m, 3H), 7.70 (t, 1H), 7.79(d, J=8 Hz, 1H), 7.92 (d, 1H), 7.98 (d, 1H), 8.12 (d, J=7.2 Hz, 2H),9.11 (s, 2H), 9.37 (s, 1H), 9.49 (s, 1H); ESIMS found for C₃₁H₂₇N₇O m/z514.0 (M+H).

N-Isopropyl-5-(3-(4-(piperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-amine156

¹H NMR (DMSO-d₆, 400 MHz) δ ppm 1.35 (d, J=6.4 Hz, 6H), 1.94 (brs, 2H),2.25 (brs, 4H), 3.92 (sep, J=6.4 Hz, 1H), 4.18 (brs, 4H), 7.54 (t, J=7.6Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.91 (s, 2H),8.06 (s, 2H), 8.45 (s, 1H), 9.04 (s, 1H); ESIMS found for C₂₇H₂₉N₇ m/z452.3 (M+H).

3-(4-(Piperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole158

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.97 (brs, 3H), 2.16 (brs, 2H), 2.32 (brs,6H), 2.70 (brs, 1H), 3.43 (d, J=5.2 Hz, 2H), 3.76 (brs, 2H), 4.11 (brs,4H), 7.58 (d, J=6.8 Hz, 1H), 7.74 (d, J=7.2 Hz, 1H), 7.88 (d, J=7.6 Hz,1H), 7.96 (s, 1H), 8.14 (d, J=4.4 Hz, 1H), 9.19 (brs, 1H), 9.37 (brs,1H), 9.58 (brs, 1H), 9.62 (brs, 1H); ESIMS found for C₂₉H₃₁N₇ m/z 478.2(M+H).

N-(5-(3-(4-(Piperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide162

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.02 (t, J=7.2 Hz, 3H), 1.48 (sex, J=7.6Hz, 2H), 1.66-1.81 (m, 4H), 1.88-2.00 (m, 2H), 2.48 (t, J=7.6 Hz, 2H),3.51 (brs, 4H), 4.63 (brs, 2H), 6.77 (d, 1H), 7.20 (q, J=7.6 Hz, 1H),7.20-7.28 (m, 1H), 7.79 (dq, J=7.6 Hz, J=1.6 Hz, 2H), 8.51 (s, 1H), 8.71(d, J=1.6 Hz, 1H), 8.77 (d, J=2.4 Hz, 1H), 8.93 (s, 1H); ESIMS found forC₂₉H₃₁N₇O m/z 494.2 (M+H).

N-(5-(3-(4-(Piperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide166

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.23 (m, 3H), 1.51 (q, J=10.8 Hz, 2H),1.67 (d, J=11.6 Hz, 1H), 1.78 (d, J=10.8 Hz, 4H), 1.90 (d, J=11.6 Hz,2H), 2.13 (brs, 4H), 2.46 (t, J=12 Hz, 1H), 4.08 (brs, 4H), 7.38 (t, J=8Hz, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.71 (d, J=8 Hz, 1H), 7.82 (s, 2H),8.97 (d, J=2.4 Hz, 2H), 9.08 (s, 1H), 9.17 (s, 1H); ESIMS found forC₃₁H₃₃N₇O m/z 520.2 (M+H).

N-(5-(3-(4-(4-Methyl-1H-imidazol-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide179

¹H NMR (CD₃OD, 400 MHz) δ ppm 2.38 (s, 3H), 7.52 (t, 1H), 7.56-7.66 (m,3H), 7.71 (d, 1H), 7.77 (d, J=8 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.91(d, 1H), 8.15 (s, 1H), 8.20 (d, J=7.6 Hz, 2H), 8.93 (s, 1H), 9.07 (s,1H), 9.14 (s, 1H), 9.51 (s, 1H), 10.12 (s, 1H); ESIMS found forC₃₀H₂₂N₈O m/z 511.2 (M+H).

3,3-Dimethyl-N-(5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butanamide184

¹H NMR (DMSO-d₆, 400 MHz) δ ppm 1.07 (s, 9H), 2.34 (s, 2H), 2.45 (s,3H), 7.49 (t, J=8 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.75 (d, J=8 Hz, 1H),7.87 (q, J=7.6 Hz, 2H), 8.46 (s, 1H), 8.63 (s, 1H), 8.84 (s, 1H), 8.86(s, 1H), 8.97 (s, 1H), 9.99 (s, 1H), 10.68 (s, 1H); ESIMS found forC₂₉H₂₈N₈O m/z 505.2 (M+H).

N-(5-(3-(4-(4-Methyl-1H-imidazol-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide186

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.03 (t, J=7.2 Hz, 3H), 1.49 (sex, J=7.6Hz, 2H), 1.75 (quin, J=8 Hz, 2H), 2.36 (s, 3H), 2.50 (t, J=7.6 Hz, 2H),7.26-7.43 (m, 2H), 7.44-7.57 (1H), 7.64 (d, J=8.4 Hz, 1H), 7.70 (d,J=8.4 Hz, 1H), 7.89 (brs, 1H), 8.22 (s, 1H), 8.41 (d, J=10.4 Hz, 1H),8.56 (s, 1H), 8.61 (s, 1H), 8.65 (s, 1H); ESIMS found for C₂₈H₂₆N₈O m/z491.2 (M+H).

N-(5-(3-(4-(4-Methyl-1H-imidazol-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide189

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.66-1.80 (m, 2H), 1.78-1.87 (m, 2H),1.87-2.00 (m, 2H), 2.01-2.12 (m, 2H), 2.55 (s, 3H), 3.04 (quin, J=8 Hz,1H), 7.53 (t, J=8 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.81 (d, J=8 Hz, 1H),7.90 (Abq, J=13.2 Hz, J=8.8 Hz, 2H), 8.21 (s, 1H), 8.93 (s, 1H), 9.04(s, 2H), 9.32 (s, 1H), 10.04 (d, J=1.2 Hz, 1H); ESIMS found forC₂₉H₂₆N₈O m/z 503.2 (M+H).

N-Benzyl-1-(5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine191

¹H NMR (CD₃OD, 400 MHz) δ ppm 2.33 (s, 3H), 4.36 (s, 2H), 4.44 (s, 2H),7.36-7.51 (m, 5H), 7.51-7.61 (m, 2H), 7.79 (d, J=8.8 Hz, 1H), 7.85 (d,J=9.2 Hz, 1H), 8.36 (s, 3H), 8.68 (d, J=1.6 Hz, 1H), 8.92 (s, 1H), 9.02(d, J=1.6 Hz, 1H), 9.11 (brs, 1H); ESIMS found for C₃₁H₂₆N₈ m/z 511.2(M+H).

3-(4-(4-Methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-5-(pyridin-3-yl)-1H-indazole196

¹H NMR (CD₃OD, 400 MHz) δ ppm 3.02 (s, 3H), 3.58 (brs, 4H), 3.85 (brs,4H), 6.78 (brs, 1H), 7.24 (t, J=8 Hz, 1H), 7.28 (brs, 1H), 7.62 (dd,J=7.6 Hz, J=4.8 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H),8.28 (d, J=7.6 Hz, 1H), 8.59 (d, J=4.4 Hz, 1H), 8.85 (s, 1H), 9.02 (s,1H); ESIMS found for C₂₄H₂₃N₇ m/z 410.2 (M+H).

3N-(5-(4-(4-Methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-5-(4-methylpyridin-3-yl)-1H-indazole197

¹H NMR (CD₃OD, 400 MHz) δ ppm 2.39 (s, 3H), 2.46 (s, 6H), 2.74 (brs,5H), 7.18 (brs, 2H), 7.46 (d, J=4.8 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H),7.75 (d, J=8.8 Hz, 1H), 8.44 (d, J=5.6 Hz, 1H), 8.52 (s, 2H), 8.57 (s,1H); ESIMIMS found for C₂₅H₂₅N₇ m/z 424.1 (M+H).

N-(5-(3-(4-(4-Methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide200

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.36 (s, 9H), 2.42 (s, 3H), 2.82 (s, 4H),3.67 (brs, 4H), 6.68 (brs, 1H), 7.18 (brs, 2H), 7.22-7.33 (m, 2H), 8.50(brs, 1H), 8.69 (brs, 1H), 8.77 (brs, 1H), 8.84 (brs, 1H); ESIMS foundfor C₂₉H₃₂N₈O m/z 509.2 (M+H).

N-(5-(3-(7-(5-fluoropyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)propionamide207

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.52 (brs, 2H), 1.60-1.72 (m, 4H), 2.48(s, 3H), 2.55 (brs, 5H), 2.87 (brs, 4H), 3.61-3.80 (m, 5H), 6.71 (brs,1H), 7.21 (brs, 2H), 7.78 (d, 1H), 7.85 (d, 1H), 8.23 (brs, 1H), 8.54(brs, 1H), 8.88 (brs, 1H), 8.91 (brs, 1H); ESIMS found for C₃₀H₃₄N₈O m/z507.2 (M+H).

N-(5-(3-(4-(4-Methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide209

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.05 (t, J=7.6 Hz, 3H), 1.78 (sex, J=7.6Hz, 2H), 2.45 (t, J=7.6 Hz, 2H), 2.84 (s, 3H), 3.35 (brs, 4H), 3.85(brs, 4H), 6.73 (brs, 1H), 7.17-7.28 (m, 2H), 7.77 (Abq, J=8.8 Hz, J=2.8Hz, 2H), 8.54 (brs, 1H), 8.69 (brs, 2H), 8.81 (s, 1H); ESIMS found forC₂₈H₃₀N₈O m/z 495.2 (M+H).

N-(5-(3-(4-(4-Methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopentanecarboxamide213

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.25 (d, J=8.8 Hz, 1H), 1.50-1.62 (m, 2H),1.62-1.83 (m, 6H), 1.82-1.95 (m, 2H), 2.31 (s, 3H), 2.70 (brs, 4H), 2.77(quin, 1H), 3.53 (brs, 1H), 6.55 (brs, 1H), 7.05 (brs, 2H), 7.60 (Abq,J=5.6 Hz, 2H), 8.35 (s, 1H), 8.53 (s, 1H), 8.65 b (s, 1H), 8.68 (s, 1H);ESIMS found for C₃₀H₃₂N₈O m/z 521.2 (M+H).

N-(5-(3-(1H-Benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide218

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.07 (d, J=6.4 Hz, 6H), 2.26 (sep, J=6.8Hz, 1H), 2.43 (d, J=7.6 Hz, 2H), 7.68 (dd, J=6 Hz, J=2.8 Hz, 2H), 7.95(dd, J=6.4 Hz, J=3.2 Hz, 2H), 8.01 (s, 2H), 8.98 (s, 2H), 9.09 (s, 1H),9.35 (s, 1H); ESIMS found for C₂₄H₂₂N₆O m/z 411.2 (M+H).

3-(1H-Benzo[d]imidazol-2-yl)-5-(4-methylpyridin-3-yl)-1H-indazole 221

¹H NMR (CD₃OD, 400 MHz) δ ppm 2.41 (s, 3H), 7.29 (dd, J=6 Hz, J=3.2 Hz,2H), 7.42 (d, J=4.8 Hz, 1H), 7.48 (d, 1H), 7.67 (brd, J=3.2 Hz, 2H),7.75 (d, J=8.4 Hz, 1H), 8.42 (d, J=5.2 Hz, 1H), 8.50 (s, 2H); ESIMSfound for C₂₀H₁₅N₅ m/z 326.1 (M+H).

N-(5-(3-(1H-Benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide 225

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.29 (d, J=6.8 Hz, 6H), 2.81 (sep, J=6.8Hz, 1H), 7.69 (dd, J=6.4 Hz, J=3.2 Hz, 2H), 7.96 (dd, J=6 Hz, J=3.2 Hz,2H), 8.03 (d, J=1 Hz, 2H), 9.01 (s, 1H), 9.04 (t, J=2 Hz, 1H), 9.13 (d,J=1.6 Hz, 1H), 9.39 (d, J=2 Hz, 1H); ESIMS found for C₂₃H₂₀N₆O m/z 397.1(M+H).

N-(5-(3-(1H-Benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)benzamide 227

¹H NMR (CD₃OD, 400 MHz) δ ppm 7.31 (dd, J=6 Hz, J=3.2 Hz, 2H), 7.57 (t,J=7.6 Hz, 2H), 7.64 (t, 1H), 7.70 (brs, 2H), 7.78 (d, J=8.4 Hz, 1H),7.85 (d, J=8.4 Hz, 1H), 8.04 (d, J=7.6 Hz, 2H), 8.59 (s, 1H), 8.79 (d,J=1.6 Hz, 1H), 8.84 (s, 1H), 9.01 (d, J=2 Hz, 1H); ESIMS found forC₂₆H₁₈N₆O m/z 431.1 (M+H).

N-(5-(3-(1H-Benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3,3-dimethylbutanamide232

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.05 (s, 9H), 2.34 (s, 2H), 7.56 (dd, J=6Hz, J=2.8 Hz, 2H), 7.85 (dd, J=6 Hz, J=3.2 Hz, 2H), 7.90 (s, 2H), 8.89(d, J=2 Hz, 1H), 8.93 (s, 1H), 9.04 (s, 1H), 9.31 (s, 1H); ESIMS foundfor C₂₅H₂₄N₆O m/z 425.2 (M+H).

N-(5-(3-(1H-Benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pentanamide 234

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.02 (t, J=7.2 Hz, 3H), 1.49 (sex, J=7.2Hz, 2H), 1.78 (quin, J=7.6 Hz, 2H), 2.59 (t, J=7.2 Hz, 2H), 7.70 (dd,J=6 Hz, J=3.2 Hz, 2H), 7.98 (dd, J=6 Hz, J=3.2 Hz, 2H), 8.04 (s, 2H),9.02 (s, 1H), 9.05 (s, 1H), 9.15 (s, 1H), 9.42 (d, J=2 Hz, 1H); ESIMSfound for C₂₄H₂₂N₆O m/z 411.1 (M+H).

N-(5-(3-(1H-Benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide 235

¹H NMR (CD₃OD, 400 MHz) δ ppm 0.90-0.98 (m, 2H), 1.01-1.07 (m, 2H), 1.87(quin, 1H), 7.32 (dd, J=6.4 Hz, J=3.2 Hz, 2H), 7.71 (dd, J=6 Hz, J=3.2Hz, 2H), 7.80 (q, J=8.8 Hz, 2H), 8.46 (t, J=0.4 Hz, 1H), 8.74 (d, J=2Hz, 1H), 8.82 (s, 1H), 8.83 (d, J=2.4 Hz, 1H); ESIMS found for C₂₃H₁₈N₆Om/z 395.1 (M+H).

N-(5-(3-(1H-Benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclohexanecarboxamide 238

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.14-1.40 (m, 3H), 1.48 (q, J=12 Hz, 2H),1.66 (d, J=11.6 Hz, 1H), 1.78 (d, J=12.8 Hz, 2H), 1.89 (d, J=12.4 Hz,2H), 2.60 (t, J=11.6 Hz, 1H), 7.57 (dd, J=6.4 Hz, J=3.2 Hz, 2H), 7.85(dd, J=6 Hz, J=3.6 Hz, 2H), 7.90 (s, 2H), 8.91 (s, 2H), 9.01 (s, 1H),9.26 (s, 1H); ESIMS found for C₂₆H₂₄N₆O m/z 437.1 (M+H).

1-(5-(3-(1H-Benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-N-benzylmethanamine239

¹H NMR (CD₃OD, 400 MHz) δ ppm 4.25 (s, 2H), 4.32 (s, 2H), 7.33 (dd, J=6Hz, J=3.2 Hz, 2H), 7.40-7.58 (m, 5H), 7.71 (dd, J=6 Hz, J=3.2 Hz, 2H),7.81 (d, J=8.8 Hz, 1H), 7.88 (dd, J=8.8 Hz, J=1.6 Hz, 1H), 8.40 (s, 1H),8.65 (d, J=1.6 Hz, 1H), 8.87 (s, 1H), 9.06 (d, J=2 Hz, 1H); ESIMS foundfor C₂₇H₂₂N₆ m/z 431.2 (M+H).

N-((5-(3-(4-(Thiophen-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methyl)ethanamine246

¹H NMR (DMSO-d₆, 400 MHz) δ ppm 1.12 (t, J=7.2 Hz, 3H), 2.74 (q, J=7.2Hz, 2H), 4.00 (s, 2H), 7.31 (t, J=7.6 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H),7.65 (d, J=7.2 Hz, 1H), 7.71 (dd, J=5.2 Hz, J=3.2 Hz, 1H), 7.84 (d,J=8.4 Hz, 1H), 7.92 (d, J=7.2 Hz, 1H), 8.23 (s, 1H), 8.27 (s, 1H), 8.62(d, J=1.6 Hz, 1H), 8.77 (d, J=1.6 Hz, 1H), 8.96 (d, J=2 Hz, 1H), 8.99(s, 1H); ESIMS found for C₂₆H₂₂N₆S m/z 451.1 (M+H).

N-(5-(3-(4-(Thiophen-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)isobutyramide249

¹H NMR (DMSO-d₆, 400 MHz) δ ppm 1.19 (d, J=6.8 Hz, 6H), 2.71 (sep, J=7.2Hz, 1H), 7.31 (t, J=8 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.64 (d, J=7.2Hz, 2H), 7.84 (s, 2H), 8.16 (d, J=4.4 Hz, 1H), 8.60 (brs, 1H), 8.72(brs, 2H), 8.79 (brs, 1H), 8.93 (brs, 1H); ESIMS found for C₂₇H₂₂N₆OSm/z 479.1 (M+H).

2-Phenyl-N-(5-(3-(4-(thiophen-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)acetamide250

¹H NMR (DMSO-d₆, 400 MHz) δ ppm 3.86 (s, 2H), 7.24-7.46 (m, 8H), 7.52(d, 1H), 7.63 (d, J=6 Hz, 2H), 7.89 (s, 2H), 8.11 (brs, 1H), 8.61 (brs,1H), 8.94 (brs, 2H); ESIMS found for C₃₁H₂₂N₆₀S m/z 527.1 (M+H).

N,N-Dimethyl-1-(5-(3-(4-(thiophen-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)methanamine253

¹H NMR (DMSO-d₆, 400 MHz) δ ppm 3.02 (s, 6H), 4.62 (d, J=2.8 Hz, 2H),7.42 (t, J=7.6 Hz, 1H), 7.66 (t, J=7.2 Hz, 2H), 7.78 (dd, J=4.8 Hz,J=3.2 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 8.02 (d, J=4.8 Hz, 1H), 8.10 (d,J=8.8 Hz, 1H), 8.56 (s, 1H), 9.10 (s, 2H), 9.23 (s, 1H), 9.47 (s, 1H),11.77 (brs, 1H); ESIMS found for C₂₆H₂₂N₆S m/z 451.1 (M+H).

5-(5-(Pyrrolidin-1-ylmethyl)pyridin-3-yl)-3-(4-(thiophen-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazole254

¹H NMR (CD₃OD, 400 MHz) δ ppm 2.17 (brs, 2H), 2.30 (brs, 2H), 3.33 (s,2H), 3.39 (brs, 2H), 3.60 (brs, 2H), 7.61 (d, J=4 Hz, 1H), 7.67-7.79 (m,3H), 7.97-8.10 (m, 3H), 8.18 (d, J=8.4 Hz, 1H), 9.13 (s, 1H), 9.15 (s,1H), 9.52 (s, 1H), 9.61 (s, 1H); ESIMS found for C₂₈H₂₄N₆S m/z 477.1(M+H).

N-(5-(3-(4-(Thiophen-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclobutanecarboxamide260

ESIMS found for C₂₈H₂₂N₆₀S m/z 491.1 (M+H).

5-(3-(4-(Furan-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-amine 267

¹H NMR (CD₃OD, 400 MHz) δ ppm 7.03 (s, 1H), 7.57-7.69 (m, 2H), 7.75 (s,1H), 7.81 (d, 1H), 7.93 (Abq, 2H), 8.05 (d, J=2 Hz, 1H), 8.10 (s, 1H),8.33 (s, 1H), 8.43 (s, 1H), 8.77 (s, 1H); ESIMS found for C₂₃H₁₆N₆O m/z393.0 (M+H).

N-(5-(3-(4-(Furan-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)pivalamide272

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.40 (s, 9H), 7.20 (brs, 1H), 7.33 (t,J=7.6 Hz, 1H), 7.49 (d, J=6.8 Hz, 1H), 7.53 (brs, 1H), 7.66 (s, 1H), Abq(7.80 [d, J=9.2 Hz, 1H], 7.86 [dd, J=8.4 Hz, J=1.6 Hz, 1H]), 8.58 (s,1H), 8.75 (d, J=2 Hz, 2H), 8.84 (d, J=6.4 Hz, 1H), 8.96 (s, 1H); ESIMSfound for C₂₈H₂₄N₆O₂ m/z 477.2 (M+H).

5-(3-(4-(Furan-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)-N-isopropylpyridin-3-amine276

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.32 (d, J=6.4 Hz, 6H), 3.83 (sep, J=6 Hz,1H), 7.20 (brs, 1H), 7.32 (t, J=7.6 Hz, 1H), 7.41 (t, J=2.4 Hz, 1H),7.49 (d, J=6.8 Hz, 1H), 7.50 (brs, 1H), 7.66 (s, 1H), Abq (7.74 [d,J=8.4 Hz, 1H], 7.80 [dd, J=8.4 Hz, J=1.6 Hz, 1H]), 7.95 (d, J=2.4 Hz,1H), 7.17 (d, J=2 Hz, 1H), 8.78 (brs, 1H), 8.88 (brs, 1H); ESIMS foundfor C₂₆H₂₂N₆O m/z 435.1 (M+H).

3-(4-(Furan-3-yl)-1H-benzo[d]imidazol-2-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole279

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.85-2.03 (m, 4H), 2.90 (s, 4H), 3.62 (d,J=10.4, 2H), 4.64 (s, 2H), 7.01 (s, 1H), 7.63-7.73 (m, 2H), 7.76 (s,1H), 7.92 (d, J=5.2 Hz, 1H), Abq (7.99 [d, J=9.2 Hz, 1H], 8.11 [d, J=8.8Hz, 1H]), 8.33 (s, 1H), 8.97 (s, 1H), 9.01 (s, 1H), 9.24 (s, 1H), 9.36(s, 1H); ESIMS found for C₂₉H₂₆N₆O m/z 475.2 (M+H).

N-(5-(3-(4-(Furan-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)butyramide281

¹H NMR (CD₃OD, 400 MHz) δ ppm 1.08 (t, J=7.6 Hz, 3H), 1.82 (sex, J=7.2Hz, 2H), 2.48 (t, J=7.6 Hz, 2H), 7.20 (brs, 1H), 7.33 (t, J=7.6 Hz, 1H),7.66 (s, 1H), 7.82 (q, J=8.8 Hz, 2H), 8.57 (s, 1H), 7.73 (s, 1H), 8.80(s, 1H), 8.94 (s, 1H); ESIMS found for C₂₇H₂₂N₆O₂ m/z 463.2 (M+H).

N-(5-(3-(4-(Furan-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazol-5-yl)pyridin-3-yl)cyclopropanecarboxamide283

¹H NMR (CD₃OD, 400 MHz) δ ppm 0.73-0.87 (m, 2H), 0.87-0.99 (m, 2H), 1.76(quin, J=4 Hz, 1H), 7.08 (brs, 1H), 7.20 (t, J=7.6 Hz, 1H), 7.37 (d,J=7.6 Hz, 1H), 7.54 (s, 1H), 7.68 (q, J=8.8 Hz, 2H), 8.46 (s, 1H), 8.59(s, 1H), 8.65 (s, 1H), 8.81 (s, 1H); ESIMS found for C₂₇H₂₀N₆O₂ m/z461.1 (M+H).

Example 2

The above synthesized compounds were screened using the assay procedurefor Wnt activity described below.

Reporter cell lines were generated by stably transducing cells of cancercell lines (e.g., colon cancer) with a lentiviral construct that includea wnt-responsive promoter driving expression of the firefly luciferasegene.

Lentiviral constructs were made in which the SP5 promoter, a promoterhaving eight TCF/LEF binding sites derived from the SP5 promoter, waslinked upstream of the firefly luciferase gene. The lentiviralconstructs included a hygromycin resistance gene as a selectable marker.The SP5 promoter construct was used to transduce SW480 cells, a coloncancer cell line having a mutated APC gene that generates a truncatedAPC protein, leading to de-regulated accumulation of β-catenin. Acontrol cell line was generated using another lentiviral constructcontaining the luciferase gene under the control of the SV40 promoterwhich does not require (β-catenin for activation.

Cultured SW480 cells bearing a reporter construct were distributed atapproximately 10,000 cells per well into 384 well multiwell plates.Compounds were then added to the wells in half-log dilutions using athree micromolar top concentration. A series of control wells for eachcell type received only buffer and compound solvent. Twenty-four hoursafter the addition of compound, reporter activity for luciferases wasassayed, for example, by addition of the BrightGlo luminescence reagent(Promega) and the Victor3 plate reader (Perkin Elmer). Readings werenormalized to DMSO only treated cells, and normalized activities werethen used for the IC₅₀ calculations. Table 2 shows the activity ofselected compounds as provided herein.

TABLE 2 Wnt inhibition Compound (μM) 1 0.002 4 0.004 5 0.034 7 0.008 90.25 10 0.069 13 0.011 16 0.031 18 0.03 19 0.005 21 0.05 22 0.18 260.179 29 0.1 32 0.035 33 0.034 35 0.161 38 0.153 41 0.015 42 0.033 430.043 44 0.14 45 0.11 46 0.225 47 0.45 54 0.046 57 0.006 57 0.116 590.332 63 0.01 66 4 69 0.023 72 1.14 75 0.006 77 0.063 79 0.045 84 0.01388 0.135 89 0.004 90 0.011 92 0.008 94 0.121 95 0.163 104 0.065 106 1.93108 0.016 110 0.205 114 0.067 116 0.023 117 0.054 118 1.46 122 0.011 1250.054 127 0.032 129 0.021 133 0.127 134 0.219 138 0.018 140 0.008 1420.155 144 1.18 146 0.058 151 0.041 155 0.289 156 0.066 158 0.116 1620.14 166 0.445 173 0.046 179 0.01 184 0.115 186 0.006 189 0.013 1910.138 196 0.028 197 0.249 200 0.076 202 0.248 207 0.801 209 0.061 2130.195 218 0.037 220 0.165 221 0.317 222 0.235 225 0.028 227 0.099 2320.065 234 0.123 235 0.025 238 0.147 239 0.372 246 0.014 249 0.013 2500.159 250 0.018 253 0.007 254 0.002 267 4.15 272 0.159 276 0.016 2790.418 281 0.025 283 0.057

The term “comprising” as used herein is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps.

What is claimed is:
 1. A compound, or pharmaceutically acceptable saltthereof, of Formula I:

wherein: R¹ is -pyridinylR³R⁴; R² is -pyridinylR⁵; R³ is 1 substituentattached to the heteroaryl ring and is selected from the groupconsisting of H, C₁₋₃ alkyl, —CF₃, —NR⁹R¹⁰, —NHC(═O)R, and —(C₁₋₃alkyl)NR⁹R¹⁰; R⁴ is 1 substituent attached to the pyridinyl ring and isselected from the group consisting of H, C₁₋₃ alkyl, —CF₃, halide, —CN,—OR⁸, —OH, —(C₁₋₃ alkyl)OR⁸, —NR⁹R¹⁰, —(C₁₋₃ alkyl)NR⁹R¹⁰ and —OCF₃; R⁵is 1-3 substituents attached to the pyridinyl ring and each isindependently selected from the group consisting of H, C₁₋₃ alkyl, —CF₃,halide, —CN, —OR⁸, —OH, —(C₁₋₃ alkyl)OR⁸, —NR⁹R¹⁰, —(C₁₋₃ alkyl)NR⁹R¹⁰and —OCF₃; each R⁸ is independently selected from the group consistingof C₁₋₉ alkyl, -arylR¹⁴, carbocyclylR¹¹, —(C₁₋₃ alkyl)arylR¹⁴ and —(C₁₋₃alkyl)carbocyclylR¹¹; each R⁹ is independently selected from the groupconsisting of H, C₁₋₆ alkyl, -arylR¹⁴, carbocyclylR¹¹, —(C₁₋₃alkyl)arylR¹⁴ and —(C₁₋₃ alkyl)carbocyclylR¹¹; each R¹⁰ is independentlyselected from the group consisting of H and C₁₋₆ alkyl; R¹¹ is 1-3substituents attached to the carbocyclyl ring and each independentlyselected from the group consisting of H, C₁₋₃ alkyl, —CF₃, halide, —CN,—O(R¹⁰), —(C₁₋₃ alkyl)OR¹⁰, —N(R¹⁰)₂, —(C₁₋₃ alkyl)N(R¹⁰)₂ and —OCF₃;R¹⁴ is 1-3 substituents attached to the aryl ring and each isindependently selected from the group consisting of H, C₁₋₃ alkyl, —CF₃,halide, —CN, —O(R¹⁰), —(C₁₋₃ alkyl)OR¹⁰, —N(R¹⁰)₂, —(C₁₋₃ alkyl)N(R¹⁰)₂and —OCF₃; with the proviso that a compound of Formula I is not:


2. The compound of claim 1, wherein R¹ is pyridin-3-ylR³R⁴.
 3. Thecompound of claim 2, wherein R³ and R⁴ are both H.
 4. The compound ofclaim 2, wherein R³ is —C₁₋₂ alkyl and R⁴ is H.
 5. The compound of claim2, wherein R³ is —CH₂NR⁹R¹⁰.
 6. The compound of claim 5, wherein R⁹ is—C₁₋₂ alkyl; R¹⁰ is —(C₁₋₂ alkyl); and R⁴ is H.
 7. The compound of claim5, wherein R⁴ and R¹⁰ are both H; and R⁹ is selected from the groupconsisting of —C₁₋₂ alkyl, —CH₂phenyl and —CH₂carbocyclyl.
 8. Thecompound of claim 2, wherein R³ is —NHC(═O)R⁸.
 9. The compound of claim8, wherein R⁴ is H and R⁸ is selected from the group consisting of —C₁₋₅alkyl, —CH₂phenyl, phenyl and -carbocyclyl.
 10. The compound of claim 2,wherein R³ is —NR⁹R¹⁰.
 11. The compound of claim 2, wherein R³ is —NH₂and R⁴ is H.
 12. The compound of claim 10, wherein R⁹ is —C₁₋₂ alkyl;R¹⁰ is —C₁₋₂ alkyl; and R⁴ is H.
 13. The compound of claim 10, whereinR⁴ and R⁹ are both H; and R¹⁰ is —C₁₋₄ alkyl.
 14. The compound of claim2, wherein R³ is selected from the group consisting of: H,


15. The compound of claim 1, wherein the compound of Formula (I) isselected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 16. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable excipient.